Pharmaceutical composition comprising an AChE inhibitor and a mGluR2 antagonist

ABSTRACT

The present invention relates to a pharmaceutical composition comprising an inhibitor of acetylcholinesterase (AChE inhibitor) and a metabotropic glutamate receptor 2 antagonist (mGluR2 antagonist) and a pharmaceutically acceptable excipient. The invention also relates to a method of treating and/or preventing acute and/or chronic neurological disorders comprising administering to a patient in need of such treatment and/or prevention a therapeutically effective amount of said AChE inhibitor and mGluR2 antagonist as well as a kit comprising said AChE inhibitor and mGluR2 antagonist. In particular, the mGluR2 antagonist relates to the compound of formula I 
                         
wherein, R 1 , R 2 , R 3 , X and Y are described hereinabove. The combination of the AChE inhibitor and mGluR2 antagonist is useful for treating and/or preventing chronic neurological disorders. These disorders include Alzheimer&#39;s disease and mild cognitive impairment.

FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition comprisingan inhibitor of acetylcholinesterase (AChE inhibitor) and a metabotropicglutamate receptor 2 antagonist (mGluR2 antagonist) and apharmaceutically acceptable excipient. The invention also relates to amethod of treating and/or preventing acute and/or chronic neurologicaldisorders comprising administering to a patient in need of suchtreatment and/or prevention a therapeutically effective amount of saidAChE inhibitor and mGluR2 antagonist as well as a kit comprising saidAChE inhibitor and mGluR2 antagonist. In particular, the mGluR2antagonist useful in compositions and methods of the invention have theformula I

wherein, R¹, R², R³, X and Y are described hereinbelow. The combinationof the AChE inhibitor of the invention and mGluR2 antagonist is usefulfor treating and/or preventing chronic neurological disorders. Thesedisorders include Alzheimer's disease. These disorders also include mildcognitive impairment.

BACKGROUND OF THE INVENTION

In the central nervous system (CNS) the transmission of stimuli takesplace by the interaction of a neurotransmitter, which is sent out by aneuron, with a neuroreceptor. L-glutamic acid, the most commonlyoccurring neurotransmitter in the CNS, plays a critical role in a largenumber of physiological processes. The glutamate-dependent stimulusreceptors are divided into two main groups. The first main group formsligand-controlled ion channels. The metabotropic glutamate receptors(mGluR) form the second main group and, furthermore, belong to thefamily of G-protein-coupled receptors.

At present, eight different members of these mGluR are known and ofthese some even have sub-types. On the basis of structural parameters,the different influences on the synthesis of secondary metabolites andthe different affinity to low-molecular weight chemical compounds, theseeight receptors can be sub-divided into three sub-groups: mGluR1 andmGluR5 belong to group I, mGluR2 and mGluR3 belong to group II andmGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.

Ligands of metabotropic glutamate receptors belonging to the group IIcan be used for the treatment or prevention of acute and/or chronicneurological disorders such as psychosis, schizophrenia, Alzheimer'sdisease, cognitive disorders and memory deficits.

Other treatable indications in this connection are restricted brainfunction caused by bypass operations or transplants, poor blood supplyto the brain, spinal cord injuries, head injuries, hypoxia caused bypregnancy, cardiac arrest and hypoglycemia. Further treatableindications are chronic and acute pain, Huntington's chorea, amyotrophiclateral sclerosis (ALS), dementia caused by AIDS, eye injuries,retinopathy, idiopathic parkinsonism or parkinsonism caused bymedicaments as well as conditions which lead to glutamate-deficiencyfunctions, such as e.g. muscle spasms, convulsions, migraine, urinaryincontinence, nicotine addiction, opiate addiction, anxiety, vomiting,dyskinesia and depressions.

SUMMARY OF THE INVENTION

An aspect of the present invention relates to a pharmaceuticalcomposition comprising an inhibitor of acetylcholinesterase (ACHEinhibitor) and a metabotropic glutamate receptor 2 antagonist (mGluR2antagonist) and a pharmaceutically acceptable excipient. Another aspectof this invention is a method of treating and/or preventing acute and/orchronic neurological disorders comprising administering to a patient inneed of such treatment and/or prevention an effective amount of saidAChE inhibitor and a mGluR2 antagonist. Yet another method aspect ofthis invention is a kit comprising said AChE inhibitor and a mGluR2antagonist.

In particular, the mGluR2 antagonist relates to the compound of formulaI

wherein,

-   X is a single bond or an ethynediyl group;-   Y is —CH═ or ═N—;-   R¹ is, in case X is a single bond, selected from hydrogen, cyano,    halogen, (C₁–C₇)-alkyl, (C₁–C₇)-alkoxy, fluoro-(C₁–C₇)-alkyl,    fluoro-(C₁–C₇)-alkoxy, pyrrol-1-yl, unsubstituted phenyl, and phenyl    substituted by one or two substituents selected from the group    consisting of halogen, (C₁–C₇)-alkyl and fluoro-(C₁–C₇)-alkyl; or-   R¹ is, in case X is an ethynediyl group, selected from unsubstituted    phenyl, and phenyl substituted by one or two substituents selected    from the group consisting of halogen, (C₁–C₇)-alkyl and    fluoro-(C₁–C₇)-alkyl;-   R² is selected from hydrogen, (C₁–C₇)-alkyl, (C₂–C₇)-alkenyl,    (C₁–C₇)-alkoxy, halogen, —NR′R″, pyrrolidin-1-yl, piperidin-1-yl,    morpholine-4-yl, fluoro-(C₁–C₇)-alkyl, fluoro-(C₁–C₇)-alkoxy, and    (C₁–C₇)-alkoxy-(ethoxy)_(m); wherein m is 1, 2, 3 or 4; R′ and R″    are each, independently selected from hydrogen, (C₁–C₇)-alkyl and    (C₃–C₇)-cycloalkyl; and-   R³ is a six-membered aromatic heterocycle ring containing 1 to 3    nitrogen atoms or a pyridine-N-oxide, which ring is unsubstituted or    substituted by one or two substituents selected from the group    consisting of halogen, fluoro-(C₁–C₇)-alkyl, fluoro-(C₁–C₇)-alkoxy,    cyano, amino, (C₁–C₇)-alkylamino, (C₁–C₇)-dialkylamino,    (C₁–C₇)-alkoxy-(C₁–C₇)-alkylamino,    (C₁–C₇)-hydroxy-(C₁–C₇)-alkylamino, —(CH₂)_(n)—C(O)—OR″,    —(CH₂)_(n)—C(O)—NR′R″, —(CH₂)_(n)—SO₂—NR′R″, —(CH₂)_(n)—C(NH₂)═NR″,    hydroxy, (C₁–C₇)-alkoxy, (C₁–C₇)-alkylthio, C₃–C₇-cycloalkyl,    (C₁–C₇)-alkyl, and (C₁–C₇)-alkyl substituted by a group consisting    of fluoro, —NR′R″, hydroxy, (C₁–C₇)-alkoxy, pyrrolidin-1-yl,    azetidin-1-yl, cyano and carbamoyloxy, wherein n is 0, 1, 2, 3 or 4;    and R′ and R″ have the meanings specified above;-   or a pharmaceutically acceptable addition salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

Non-limiting examples of AChE inhibitors include donepezil (Aricept),rivastigmine (Exelon), metrifonate (Promem), galantamine (Reminyl),physostigmine, tacrine (Cognex), fordine (Huperzine A), phenserine,citicoline (Neurox) and ganstigmine.

In a preferred embodiment, the AChE inhibitor is donepezil (Aricept) ora prodrug thereof, or a pharmaceutically acceptable salt or solvate ofsaid compound or prodrug.

The AChE inhibitor and the mGluR2 antagonist may be administeredseparately, sequentially or simultaneously. Where the AChE inhibitor andthe mGluR2 antagonist are administered simultaneously, they may beadministered either in the same composition or in differentcompositions.

Acute and/or chronic neurological disorders include psychosis,schizophrenia, Alzheimer's disease, cognitive disorders and memorydeficits like mild cognitive impairment, age-related cognitive decline,vascular dementia, Parkinsons's disease, memory impairment associatedwith depression or anxiety, Down's syndrome, stroke, traumatic braininjury, and attention deficit disorder. Other treatable indications arerestricted brain function caused by bypass operations or transplants,poor blood supply to the brain, spinal cord injuries, head injuries,hypoxia caused by pregnancy, cardiac arrest and hypoglycemia. Furthertreatable indications are acute and chronic pain, Huntington's chorea,ALS, dementia caused by AIDS, eye injuries, retinopathy, idiopathicparkinsonism or parkinsonism caused by medicaments as well as conditionswhich lead to glutamate-deficient functions, such as e.g. muscle spasms,convulsions, migraine, urinary incontinence, nicotine addiction,psychotic episodes, opiate addiction, anxiety, vomiting, dyskinesia anddepression.

In a preferred embodiment, the acute and/or chronic neurologicaldisorder is Alzheimer's disease. In another preferred embodiment, theacute and/or chronic neurological disorder is mild cognitive impairment.

As used herein, a mammal in need of treatment of an acute and/or chronicneurological disorder means a mammal, and preferably a human, that issuffering from, or is at risk of suffering from, an acute and/or chronicneurological disorder.

As used herein, the terms “treat”, treating” and treatment”, and thelike, as applied to an acute and/or chronic neurological disorder, referto methods that slow, ameliorate, reduce or reverse such a disorder orany symptoms associated with said disorder, as currently afflicting thesubject, as well as methods that prevent such a disorder or any symptomsthereof, from occurring.

The present invention further provides the use of an AChE inhibitor anda mGluR2 antagonist in the manufacture of a pharmaceutical composition(medicament) for treating an acute and/or chronic neurological disorder.The mGluR2 antagonist and an AChE inhibitor may be combined in a singlemedicament or maintained in separate medicaments.

In another embodiment the present invention provides a compositioncomprising an AChE inhibitor and a mGluR2 antagonist, e.g. adihydro-benzo[b][1,4]diazepin-2-one derivative. In still anotherembodiment the present invention provides a composition comprising anAChE inhibitor and a compound of formula I as defined above.

The compounds of formula I can also be used in form of their prodrugs.Examples are esters, N-oxides, phosphate esters, glycoamide esters,glyceride conjugates and the like. The prodrugs may add to the value ofthe active compounds advantages in absorption, pharmacokinetics indistribution and transport to the brain.

All tautomeric forms of the compounds of formula I are also embracedherewith.

Unless otherwise stated, the following terms used in the presentdescription have the definitions given in the following.

The term “ethynediyl group” denotes a group that contains a triple bondbetween two carbon atoms.

The term “(C₁–C₇)-alkyl” denotes straight-chain or branched saturatedhydrocarbon residues with 1 to 7 carbon atoms, preferably with 1 to 4carbon atoms, such as methyl, ethyl, n-propyl, i-propyl and the like.

The term “(C₂–C₇)-alkenyl” denotes straight-chain or branchedunsaturated hydrocarbon residues with 2 to 7 carbon atoms, preferablywith 2 to 4 carbon atoms, such as ethenyl or propenyl.

The term “(C₁–C₇)-alkoxy” denotes a (C₁–C₇)-alkyl residue in the senseof the foregoing definition bound via an oxygen atom. Examples of“(C₁–C₇)-alkoxy” residues include methoxy, ethoxy, isopropoxy and thelike.

The term “halogen” embraces fluorine, chlorine, bromine and iodine.

The term “fluoro-(C₁–C₇)-alkyl” means a (C₁–C₇)-alkyl residue, whereinone or more hydrogen atoms are replaced by fluorine, for exampletrifluoromethyl. Accordingly, the term “fluoro-(C₁–C₇)-alkoxy” denotes a(C₁–C₇)-alkoxy residue as defined before, wherein one or more hydrogenatoms are replaced by fluorine.

“(C₁–C₇)-alkoxy-(ethoxy)_(m)” (m is 1, 2, 3 or 4) denotes a(C₁–C₇)-alkoxy residue in the sense of the foregoing definition boundvia 1 to 4 —CH₂—CH₂—O— groups, e.g. 2-meth-oxy-ethoxy.

The term “C₃–C₇-cycloalkyl” means a cycloalkyl group containing 3 to 7carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl.

The term “alkylthio” denotes a (C₁–C₇)-alkyl residue in the sense of theforegoing definition bound via an sulfur atom, for examplemethylsulfanyl.

It will be understood that the above residues may bear substituents,e.g. alkyl in the meaning of R² may be unsubstituted or substituted byOH; alkoxy in the meaning of R² may be unsubstituted or substituted bycycloalkyl, e.g. by cyclopropyl, or by alkoxy, e.g. methoxy.

“Carbamoyloxy” means the group —O—CO—NH₂.

The expression “six-membered aromatic heterocycle containing 1 to 3nitrogen atoms” means a six-membered heteroaryl group selected from thegroup consisting of pyridine, pyridazine, pyrimidine, pyrazine andtriazine.

“Pyridine-N-oxide” or “pyridine-1-oxide” means a compound having theformula:

The term “pharmaceutically acceptable addition salt” refers to any saltderived from an inorganic or organic acid or base.

The term “therapeutically effective amount” refers to an amount of atleast one AChE inhibitor and mGluR2 antagonist (or that of the compoundof formula I) or a pharmaceutically acceptable salt thereof, thatmodulates the glutamate receptors.

The term “pharmaceutically acceptable excipient” refers to apharmaceutically acceptable carrier, vehicle, diluent, adjustment, orsimilar mechanism for delivering a pharmaceutical composition.

In one embodiment the composition comprises a compound of formula Iwherein X is a single bond.

In one embodiment the composition of the invention comprises a compoundof formula I wherein R¹ is hydrogen, halogen, e.g. Cl or F,(C₁–C₇)-alkyl, e.g. CH₃, fluoro-(C₁–C₇)-alkyl, e.g. CF₃,fluoro-(C₁–C₇)-alkoxy, e.g. OCF₃ or OCH₂CF₃, pyrrol-1-yl or phenyl,which is unsubstituted or substituted by halogen, e.g. fluorophenyl,e.g. 2-fluorophenyl or 4-fluorophenyl. In another aspect the compositionof the invention comprises a compound of formula I wherein R¹ ishalogen, e.g. Cl or F, fluoro-(C₁–C₇)-alkyl, e.g. CF₃,fluoro-(C₁–C₇)-alkoxy, e.g. OCF₃, or phenyl, which is substituted byhalogen, e.g. fluorophenyl, e.g. 2-fluorophenyl.

In one embodiment the composition of the invention comprises a compoundof formula I wherein R² is hydrogen, (C₁–C₇)-alkyl, e.g. CH₃, CH₂OH,CH₂CH₃ or CH₂CH₂CH₃, (C₂–C₇)-alkenyl, e.g. ethenyl, (C₁–C₇)-alkoxy, e.g.OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OCH₂cyclopropyl or OCH₂CH₂OCH₃, halogen, e.g.Cl or F, fluoro-(C₁–C₇)-alkyl, e.g. CF₃, fluoro-(C₁–C₇)-alkoxy, e.g.OCH₂CF₃, (C₃–C₇)-cycloalkyl, e.g. cyclopropyl, pyrrolidinyl, e.g.pyrrolidin-1-yl, morpholinyl, e.g. morpholin-4-yl, or —NR′R″, wherein R′and R″ are each independently hydrogen or (C₁–C₇)-alkyl, e.g. methyl,propyl or butyl, e.g. N(CH₃)₂, NHCH₂CH(CH₃)₂, N(CH₃)CH₂CH₂(CH₃)₂,N(CH₃)CH₂(CH₃)₂ or N(CH₃)CH₂CH₂CH₃. In another aspect the composition ofthe invention comprises a compound of formula I wherein R² is hydrogen,(C₁–C₇)-alkyl, e.g. CH₃ or CH₂CH₃, (C₁–C₇)-alkoxy, e.g. OCH₃, OCH₂CH₃ orOCH₂cyclopropyl, halogen, e.g. Cl, fluoro-(C₁–C₇)-alkyl, e.g. CF₃,fluoro-(C₁–C₇)-alkoxy, e.g. OCH₂CF₃, or —NR′R″ wherein R′ and R″ are(C₁–C₇)-alkyl, e.g. methyl, e.g. N(CH₃)₂.

In one aspect the composition of the invention comprises a compound offormula I wherein R³ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,[1,2,4]triazinyl or a pyridine-N-oxide, e.g. 1-oxy-pyridinyl, which areunsubstituted or substituted by one or two substituents selected fromthe group consisting of halogen, fluoro-(C₁–C₇)-alkoxy, cyano, amino,(C₁–C₇)-alkylamino, (C₁–C₇)-dialkylamino,(C₁–C₇)-alkoxy-(C₁–C₇)-alkylamino, (C₁–C₇)-hydroxy-(C₁–C₇)-alkylamino,—(CH₂)_(n)—C(O)—OR″, —(CH₂)_(n)—C(O)—NR′R″, —(CH₂)_(n)—SO₂—NR′R″,—(CH₂)_(n)—C(NH₂)═NR″, hydroxy, (C₁–C₇)-alkoxy, (C₁–C₇)-alkylthio,C₃–C₇-cycloalkyl, and (C₁–C₇)-alkyl, which is optionally substituted byfluoro, —NR′R″, hydroxy, (C₁–C₇)-alkoxy, pyrrolidin-1-yl, azetidin-1-yl,cyano or carbamoyloxy, wherein n is 0, 1, 2, 3 or 4; and R′ and R″ havethe meanings specified above.

Examples for pyridinyl are pyridin-2-yl,6-methylpyridin-2-yl,:pyridin-3-yl, 6-cyanopyridin-3-yl,6-aminopyridin-3-yl, 6-dimethylaminopyridin-3-yl, 6-methoxypyridin-3-yl,6-cyclopropylpyridin-3-yl, 6-methylpyridin-3-yl, 2-methylpyridin-3-yl,4-methylpyridin-3-yl, 2,6-dimethylpyridin-3-yl,4,6-dimethylpyridin-3-yl, 2-ethylpyridin-3-yl, 6-ethylpyridin-3-yl,4-methyl-6-ethylpyridin-3-yl, 6-isopropylpyridin-3-yl,2-isopropylpyridin-3-yl, 4-methyl-6-cyclopropylpyridin-3-yl,pyridin-4-yl, 2-methylpyridin-4-yl, 2-ethylpyridin-4-yl,2-isopropylpyridin-4-yl, 2-isobutylpyridin-4-yl,2-hydroxymethylpyridin-4-yl, 2-hydroxymethyl-6-methylpyridin-4-yl,2-trifluoromethylpyridin-4-yl, 2,3-dimethylpyridin-4-yl,2,6-dimethylpyridin-4-yl, 3,6-dimethylpyridin-4-yl,2-ethyl-6-methylpyridin-4-yl, 3-ethyl-6-methylpyridin-4-yl,2-cyanopyridin-4-yl, 2-cyclopropylpyridin-4-yl,2-cyclopentylpyridin-4-yl, 2-cyclopropyl-6-methylpyridin-4-yl,2-morpholin-4-yl-pyridin-4-yl, 2-pyrrolidin-1-yl-pyridin-4-yl,2-[(isobutyl-methyl-amino)-methyl]-pyridin-4-yl,2-[(methyl-propyl-amino)-methyl]-pyridin-4-yl,2-cyclopropylaminomethyl-pyridin-4-yl,2-pyrrolidin-1-ylmethyl-pyridin-4-yl,2-azetidin-1-ylmethyl-pyridin-4-yl, 2-methoxymethyl-pyridin-4-yl.

Examples for pyridazinyl are pyridazin-3-yl, 6-methyl-pyridazin-3-yl,6-methoxy-pyridazin-3-yl and pyridazin-4-yl.

Examples for pyrimidinyl are pyrimidin-2-yl, pyrimidin-4-yl,2-methylpyrimidin-4-yl, 6-methylpyrimidin-4-yl,2-amino-6-methylpyrimidin-4-yl, 2-methylamino-6-methylpyrimidin-4-yl,2-dimethylamino-6-methylpyrimidin-4-yl,2-hydroxyethylamino-6-methylpyrimidin-4-yl,2-(2-methoxy-ethylamino)-6-methyl-pyrimidin-4-yl,2-morpholin-4-yl-6-methyl-pyrimidin-4-yl, 6-aminopyrimidin-4-yl,6-methylaminopyrimidin-4-yl, 6-dimethylaminopyrimidin-4-yl,6-(2-methoxy-ethylamino)-pyrimidin-4-yl, and pyrimidin-5-yl.

Examples for pyrazinyl are pyrazin-2-yl and 6-methyl-pyrazin-2-yl.

Examples for [1,2,4]triazinyl are [1,2,4]triazin-3-yl,(5,6-dimethyl-[1,2,4]triazin-3-yl), (3-methyl-[1,2,4]triazin-6-yl and[1,2,4]triazin-6-yl. Examples for a pyridine-N-oxide are1-oxy-pyridinyl, e.g. 1-oxy-pyridin-3-yl, 1-oxy-pyridin-3-yl),1-oxy-pyridin-4-yl, 2-methyl-1-oxy-pyridin-4-yl,2-hydroxymethyl-1-oxy-pyridin-4-yl and 2,6-dimethyl-1-oxy-pyridin-4-yl.

In another aspect the composition of the invention comprises a compoundof formula I wherein R³ is pyridinyl or pyrimidinyl, which areunsubstituted or substituted by one or two substituents selected fromthe group consisting of halogen, fluoro-(C₁–C₇)-alkoxy, cyano, amino,(C₁–C₇)-alkylamino, (C₁–C₇)-dialkylamino,(C₁–C₇)-alkoxy-(C₁–C₇)-alkylamino, (C₁–C₇)-hydroxy-(C₁–C₇)-alkylamino,—(CH₂)_(n)—C(O)—OR″, —(CH₂)_(n)—C(O)—NR′R″, —(CH₂)_(n)—SO₂—NR′R″,—(CH₂)_(n)—C(NH₂)═NR″, hydroxy, (C₁–C₇)-alkoxy, (C₁–C₇)-alkylthio,C₃–C₇-cycloalkyl, and (C₁–C₇)-alkyl, which is optionally substituted byfluoro, —NR′R″, hydroxy, (C₁–C₇)-alkoxy, pyrrolidin-1-yl, azetidin-1-yl,cyano or carbamoyloxy, wherein n is 0, 1, 2, 3 or 4; and R′ and R″ havethe meanings specified above. In yet another aspect the composition ofthe invention comprises a compound of formula I wherein R³ is pyridinylor pyrimidinyl, which are unsubstituted or substituted by one or twosubstituents selected from C₃–C₇-cycloalkyl and (C₁–C₇)-alkyl, which isoptionally substituted by fluoro, —NR′R″, hydroxy, (C₁–C₇)-alkoxy,pyrrolidin-1-yl, azetidin-1-yl, cyano or carbamoyloxy, wherein n is 0,1, 2, 3 or 4; and R′ and R″ have the meanings specified above. In stillanother aspect the composition of the invention comprises a compound offormula I wherein R³ is pyridinyl or pyrimidinyl, which areunsubstituted or substituted by one or two substituents selected fromC₃–C₇-cycloalkyl and (C₁–C₇)-alkyl, which is unsubstituted orsubstituted by fluoro or hydroxy. In still another aspect thecomposition of the invention comprises a compound of formula I whereinR³ is pyridin-3-yl, 6-cyclopropylpyridin-3-yl, pyridin-4-yl,2-methylpyridin-4-yl, 2-ethylpyridin-4-yl, 2-hydroxymethylpyridin-4-yl,2,6-dimethylpyridin-4-yl, 2-ethyl-6-methylpyridin-4-yl or6-methylpyrimidin-4-yl.

In another embodiment the composition of the invention comprises acompound of formula I wherein X is a single bond; Y is —CH═ or ═N—; R¹is hydrogen, cyano, halogen, (C₁–C₇)-alkyl, (C₁–C₇)-alkoxy,fluoro-(C₁–C₇)-alkyl, fluoro-(C₁–C₇)-alkoxy, pyrrol-1-yl, or phenyl,which is unsubstituted or substituted by one or two substituentsselected from the group consisting of halogen, (C₁–C₇)-alkyl orfluoro-(C₁–C₇)-alkyl; R² is hydrogen, (C₁–C₇)-alkyl, (C₂–C₇)-alkenyl,(C₁–C₇)-alkoxy, halogen, —NR′R″, pyrrolidin-1-yl, piperidin-1-yl,morpholine-4-yl, fluoro-(C₁–C₇)-alkyl, fluoro-(C₁–C₇)-alkoxy, or(C₁–C₇)-alkoxy-(ethoxy)_(m); wherein m is 1, 2, 3 or 4; R′ and R″ areeach independently hydrogen, (C₁–C₇)-alkyl or (C₃–C₇)-cycloalkyl; and R³is a six-membered aromatic heterocycle containing 1 to 3 nitrogen atomsor a pyridine-N-oxide, which rings are unsubstituted or substituted byone or two substituents selected from the group consisting of halogen,fluoro-(C₁–C₇)-alkyl, fluoro-(C₁–C₇)-alkoxy, cyano, amino,(C₁–C₇)-alkylamino, (C₁–C₇)-dialkylamino,(C₁–C₇)-alkoxy-(C₁–C₇)-alkylamino, (C₁–C₇)-hydroxy-(C₁–C₇)-alkylamino,—(CH₂)_(n)—C(O)—OR″, —(CH₂)_(n)—C(O)—NR′R″, —(CH₂)_(n)—SO₂—NR′R″,—(CH₂)_(n)—C(NH₂)═NR″, hydroxy, (C₁–C₇)-alkoxy, (C₁–C₇)-alkylthio,C₃–C₇-cycloalkyl and (C₁–C₇)-alkyl, which is optionally substituted byfluoro, —NR′R″, hydroxy, (C₁–C₇)-alkoxy, pyrrolidin-1-yl, azetidin-1-yl,cyano or carbamoyloxy, wherein n is 0, 1, 2, 3 or 4; and R′ and R″ havethe meanings specified above.

In another embodiment the composition of the invention comprises acompound of formula I wherein X is a single bond; Y is ═N—; R′ ishydrogen, cyano, halogen, (C₁–C₇)-alkyl, (C₁–C₇)-alkoxy,fluoro-(C₁–C₇)-alkyl, fluoro-(C₁–C₇)-alkoxy, pyrrol-1-yl, or phenyl,which is unsubstituted or substituted by one or two substituentsselected from the group consisting of halogen, (C₁–C₇)-alkyl orfluoro-(C₁–C₇)-alkyl; R² is hydrogen, (C₁–C₇)-alkyl, (C₂–C₇)-alkenyl,(C₁–C₇)-alkoxy, halogen, —NR′R″, pyrrolidin-1-yl, piperidin-1-yl,morpholine-4-yl, fluoro-(C₁–C₇)-alkyl, fluoro-(C₁–C₇)-alkoxy, or(C₁–C₇)-alkoxy-(ethoxy)_(m); wherein m is 1, 2, 3 or 4; R′ and R″ areeach independently hydrogen, (C₁–C₇)-alkyl or (C₃–C₇)-cycloalkyl; and R³is a six-membered aromatic heterocycle containing 1 to 3 nitrogen atomsor a pyridine-N-oxide, which rings are unsubstituted or substituted byone or two substituents selected from the group consisting of halogen,fluoro-(C₁–C₇)-alkyl, fluoro-(C₁–C₇)-alkoxy, cyano, amino,(C₁–C₇)-alkylamino, (C₁–C₇)-dialkylamino,(C₁–C₇)-alkoxy-(C₁–C₇)-alkylamino, (C₁–C₇)-hydroxy-(C₁–C₇)-alkylamino,—(CH₂)_(n)—C(O)—OR″, —(CH₂)_(n)—C(O)—NR′R″, —(CH₂)_(n)—SO₂—NR′R″,—(CH₂)_(n)—C(NH₂)═NR″, hydroxy, (C₁–C₇)-alkoxy, (C₁–C₇)-alkylthio,C₃–C₇-cycloalkyl and (C₁–C₇)-alkyl, which is optionally substituted byfluoro, —NR′R″, hydroxy, (C₁–C₇)-alkoxy, pyrrolidin-1-yl, azetidin-1-yl,cyano or carbamoyloxy, wherein n is 0, 1, 2, 3 or 4; and R′ and R″ havethe meanings specified above.

In another embodiment the composition of the invention comprises acompound of formula I wherein X is a single bond; Y is ═N—; R¹ ishalogen, (C₁–C₇)-alkyl, (C₁–C₇)-alkoxy, fluoro-(C₁–C₇)-alkyl, or phenyl,which is substituted by halogen; R² is hydrogen, (C₁–C₇)-alkyl,(C₁–C₇)-alkoxy, halogen, —NR′R″, fluoro-(C₁–C₇)-alkyl,fluoro-(C₁–C₇)-alkoxy, wherein R′ and R″ are each independently(C₁–C₇)-alkyl; and R³ is pyridinyl which is unsubstituted or substitutedby one or two substituents selected from (C₁–C₇)-alkyl, which isunsubstituted or substituted by hydroxy; and R′ and R″ have the meaningsspecified above.

In another embodiment the composition of the invention comprises acompound of formula I wherein X is a single bond; Y is ═N—; R¹ isfluoro-(C₁–C₇)-alkyl; R² is (C₁–C₇)-alkyl; and R³ is pyridinyl which isunsubstituted or substituted by one or two substituents selected from(C₁–C₇)-alkyl, which is unsubstituted or substituted by hydroxy; and R′and R″ have the meanings specified above.

In still another embodiment the composition of the invention comprises acompound of formula I wherein X is a single bond; Y is ═N—; R¹ ishalogen, (C₁–C₇)-alkyl, (C₁–C₇)-alkoxy, fluoro-(C₁–C₇)-alkyl, or phenyl,which is substituted by halogen; R² is hydrogen, (C₁–C₇)-alkyl,(C₁–C₇)-alkoxy, halogen, —NR′R″, fluoro-(C₁–C₇)-alkyl,fluoro-(C₁–C₇)-alkoxy, wherein R′ and R″ are each independently(C₁–C₇)-alkyl; and R³ is pyridinyl which is unsubstituted or substitutedby (C₁–C₇)-alkyl.

In another embodiment the composition of the invention comprises acompound of formula I wherein X is a single bond; Y is ═N—; R¹ isfluoro-(C₁–C₇)-alkyl; R² is (C₁–C₇)-alkyl; and R³ is pyridinyl which isunsubstituted or substituted by (C₁–C₇)-alkyl. In yet another embodimentthe composition of the invention comprises a compound of formula Iwherein X is a single bond, Y is ═N—, R¹ is CF₃, R² is CH₃ and R³ ispyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl or2,6-dimethylpyridin-4-yl.

In one embodiment the composition of the invention comprises a compoundof formula I wherein X is a single bond; Y is —CH═; R¹ is hydrogen,cyano, halogen, (C₁–C₇)-alkyl, (C₁–C₇)-alkoxy, fluoro-(C₁–C₇)-alkyl,fluoro-(C₁–C₇)-alkoxy, pyrrol-1-yl, or phenyl, which is unsubstituted orsubstituted by one or two substituents selected from the groupconsisting of halogen, (C₁–C₇)-alkyl or fluoro-(C₁–C₇)-alkyl; R² ishydrogen, (C₁–C₇)-alkyl, (C₂–C₇)-alkenyl, (C₁–C₇)-alkoxy, halogen,—NR′R″, pyrrolidin-1-yl, piperidin-1-yl, morpholine-4-yl,fluoro-(C₁–C₇)-alkyl, fluoro-(C₁–C₇)-alkoxy, or(C₁–C₇)-alkoxy-(ethoxy)_(m); wherein m is 1, 2, 3 or 4; R′ and R″ areeach independently hydrogen, (C₁–C₇)-alkyl or (C₃–C₇)-cycloalkyl; and R³is a six-membered aromatic heterocycle containing 1 to 3 nitrogen atomsor a pyridine-N-oxide, which rings are unsubstituted or substituted byone or two substituents selected from the group consisting of halogen,fluoro-(C₁–C₇)-alkyl, fluoro-(C₁–C₇)-alkoxy, cyano, amino,(C₁–C₇)-alkylamino, (C₁–C₇)-dialkylamino,(C₁–C₇)-alkoxy-(C₁–C₇)-alkylamino, (C₁–C₇)-hydroxy-(C₁–C₇)-alkylamino,—(CH₂)_(n)—C(O)—OR″, —(CH₂)_(n)—C(O)—NR′R″, —(CH₂)_(n)—SO₂—NR′R″,—(CH₂)_(n)—C(NH₂)═NR″, hydroxy, (C₁–C₇)-alkoxy, (C₁–C₇)-alkylthio,C₃–C₇-cycloalkyl and (C₁–C₇)-alkyl, which is optionally substituted byfluoro,

—NR′R″, hydroxy, (C₁–C₇)-alkoxy, pyrrolidin-1-yl, azetidin-1-yl, cyanoor carbamoyloxy, wherein n is 0, 1, 2, 3 or 4; and R′ and R″ have themeanings specified above.

In another embodiment the composition of the invention comprises acompound of formula I wherein X is a single bond; Y is —CH═; R¹ ishalogen, (C₁–C₇)-alkyl, (C₁–C₇)-alkoxy, fluoro-(C₁–C₇)-alkyl, or phenyl,which is substituted by one or two substituents selected from the groupconsisting of halogen; R² is hydrogen, (C¹–C₇)-alkyl, (C₁–C₇)-alkoxy,halogen, —NR′R″, fluoro-(C₁–C₇)-alkyl, fluoro-(C₁–C₇)-alkoxy, wherein R′and R″ are each independently (C₁–C₇)-alkyl; and R³ is a six-memberedaromatic heterocycle containing 1 to 3 nitrogen atoms or apyridine-N-oxide, which rings are unsubstituted or substituted by one ortwo substituents selected from the group consisting of halogen,fluoro-(C₁–C₇)-alkyl, fluoro-(C₁–C₇)-alkoxy, cyano, amino,(C₁–C₇)-alkylamino, (C₁–C₇)-dialkylamino,(C₁–C₇)-alkoxy-(C₁–C₇)-alkylamino, (C₁–C₇)-hydroxy-(C₁–C₇)-alkylamino,—(CH₂)_(n)—C(O)—OR″, —(CH₂)_(n)—C(O)—NR′R″, —(CH₂)_(n)—SO₂—NR′R″,—(CH₂)_(n)—C(NH₂)═NR″, hydroxy, (C₁–C₇)-alkoxy, (C₁–C₇)-alkylthio,C₃–C₇-cycloalkyl and (C₁–C₇)-alkyl, which is optionally substituted byfluoro, —NR′R″, hydroxy, (C₁–C₇)-alkoxy, pyrrolidin-1-yl, azetidin-1-yl,cyano or carbamoyloxy, wherein n is 0, 1, 2, 3 or 4; and R′ and R″ havethe meanings specified above.

In another embodiment the composition of the invention comprises acompound of formula I wherein X is a single bond; Y is —CH═; R¹ ishydrogen, cyano, halogen, (C₁–C₇)-alkyl, (C₁–C₇)-alkoxy,fluoro-(C₁–C₇)-alkyl, fluoro-(C₁–C₇)-alkoxy, pyrrol-1-yl, or phenyl,which is unsubstituted or substituted by one or two substituentsselected from the group consisting of halogen, (C₁–C₇)-alkyl orfluoro-(C₁–C₇)-alkyl; R² is hydrogen, (C₁–C₇)-alkyl, (C₂–C₇)-alkenyl,(C₁–C₇)-alkoxy, halogen, —NR′R″, pyrrolidin-1-yl, piperidin-1-yl,morpholine-4-yl, fluoro-(C₁–C₇)-alkyl, fluoro-(C₁–C₇)-alkoxy, or(C₁–C₇)-alkoxy-(ethoxy)_(m); wherein m is 1, 2, 3 or 4; R′ and R″ areeach independently hydrogen, (C₁–C₇)-alkyl or (C₃–C₇)-cycloalkyl; and R³is pyridinyl or pyrimidinyl, which are unsubstituted or substituted byone or two substituents selected from the group consisting of halogen,fluoro-(C₁–C₇)-alkyl, fluoro-(C₁–C₇)-alkoxy, cyano, amino,(C₁–C₇)-alkylamino, (C₁–C₇)-dialkylamino,(C₁–C₇)-alkoxy-(C₁–C₇)-alkylamino, (C₁–C₇)-hydroxy-(C₁–C₇)-alkylamino,—(CH₂)_(n)—C(O)—OR″, —(CH₂)_(n)—C(O)—NR′R″, —(CH₂)_(n)—SO₂—NR′R″,—(CH₂)_(n)—C(NH₂)═NR″, hydroxy, (C₁–C₇)-alkoxy, (C₁–C₇)-alkylthio,C₃–C₇-cycloalkyl and (C₁–C₇)-alkyl, which is optionally substituted byfluoro, —NR′R″, hydroxy, (C₁–C₇)-alkoxy, pyrrolidin-1-yl, azetidin-1-yl,cyano or carbamoyloxy, wherein n is 0, 1, 2, 3 or 4; and R′ and R″ havethe meanings specified above.

In still another embodiment the composition of the invention comprises acompound of formula I wherein X is a single bond; Y is —CH═; R¹ ishydrogen, cyano, halogen, (C₁–C₇)-alkyl, (C₁–C₇)-alkoxy,fluoro-(C₁–C₇)-alkyl, fluoro-(C₁–C₇)-alkoxy, pyrrol-1-yl, or phenyl,which is unsubstituted or substituted by one or two substituentsselected from the group consisting of halogen, (C₁–C₇)-alkyl orfluoro-(C₁–C₇)-alkyl; R² is hydrogen, (C₁–C₇)-alkyl, (C₂–C₇)-alkenyl,(C₁–C₇)-alkoxy, halogen, —NR′R″, pyrrolidin-1-yl, piperidin-1-yl,morpholine-4-yl, fluoro-(C₁–C₇)-alkyl, fluoro-(C₁–C₇)-alkoxy, or(C₁–C₇)-alkoxy-(ethoxy)_(m); wherein m is 1, 2, 3 or 4; R′ and R″ areeach independently hydrogen, (C₁–C₇)-alkyl or (C₃–C₇)-cycloalkyl; and R³is pyridinyl or pyrimidinyl, which are unsubstituted or substituted byone or two substituents selected from the group consisting ofC₃–C₇-cycloalkyl and (C₁–C₇)-alkyl, which is unsubstituted orsubstituted by hydroxy.

In still another embodiment the composition of the invention comprises acompound of formula I wherein X is a single bond; Y is —CH═; R¹ ishalogen, (C₁–C₇)-alkyl, (C₁–C₇)-alkoxy, fluoro-(C₁–C₇)-alkyl, or phenyl,which is unsubstituted or substituted by one or two substituentsselected from the group consisting of halogen; R² is hydrogen,(C₁–C₇)-alkyl, (C₂–C₇)-alkenyl, (C₁–C₇)-alkoxy, halogen, —NR′R″,pyrrolidin-1-yl, piperidin-1-yl, morpholine-4-yl, fluoro-(C₁–C₇)-alkyl,fluoro-(C₁–C₇)-alkoxy, or (C₁–C₇)-alkoxy-(ethoxy)_(m); wherein m is 1,2, 3 or 4; R′ and R″ are each independently hydrogen, (C₁–C₇)-alkyl or(C₃–C₇)-cycloalkyl; and R³ is pyridinyl or pyrimidinyl, which areunsubstituted or substituted by one or two substituents selected fromthe group consisting of C₃–C₇-cycloalkyl and (C₁–C₇)-alkyl, which isunsubstituted or substituted by hydroxy.

In still another embodiment the composition of the invention comprises acompound of formula I wherein X is a single bond; Y is —CH═; R¹ ishydrogen, cyano, halogen, (C₁–C₇)-alkyl, (C₁–C₇)-alkoxy,fluoro-(C₁–C₇)-alkyl, fluoro-(C₁–C₇)-alkoxy, pyrrol-1-yl, or,phenyl,which is unsubstituted or substituted by one or two substituentsselected from the group consisting of halogen, (C₁–C₇)-alkyl orfluoro-(C₁–C₇)-alkyl; R² is hydrogen, (C₁–C₇)-alkyl, (C₁–C₇)-alkoxy,halogen, —NR′R″, fluoro-(C₁–C₇)-alkyl, fluoro-(C₁–C₇)-alkoxy; wherein R′and R″ are each independently hydrogen, (C₁–C₇)-alkyl or(C₃–C₇)-cycloalkyl; and R³ is pyridinyl or pyrimidinyl, which areunsubstituted or substituted by one or two substituents selected fromthe group consisting of C₃–C₇-cycloalkyl and (C₁–C₇)-alkyl, which isunsubstituted or substituted by hydroxy.

In still another embodiment the composition of the invention comprises acompound of formula I wherein X is a single bond; Y is —CH═; R¹ ishalogen, (C₁–C₇)-alkyl, (C₁–C₇)-alkoxy, fluoro-(C₁–C₇)-alkyl,fluoro-(C₁–C₇)-alkoxy, or phenyl, which is substituted by one or twosubstituents selected from the group consisting of halogen; R² ishydrogen, (C₁–C₇)-alkyl, (C₁–C₇)-alkoxy, halogen, —NR′R″,fluoro-(C₁–C₇)-alkyl, fluoro-(C₁–C₇)-alkoxy; wherein R′ and R″ are eachindependently (C₁–C₇)-alkyl; and R³ is pyridinyl or pyrimidinyl, whichare unsubstituted or substituted by one or two substituents selectedfrom the group consisting of C₃–C₇-cycloalkyl and (C₁–C₇)-alkyl, whichis unsubstituted or substituted by hydroxy.

In yet another embodiment the composition of the invention comprises acompound of formula I wherein X is a single bond; Y is —CH═; R¹ is Cl orF, CH₃, CF₃, OCF₃, or phenyl, which is substituted by fluoro; R² ishydrogen, methyl, ethyl, cyclopropylmethoxy, methoxyethoxy, Cl, N(CH₃)₂,CF₃, OCH₂CF₃; and R³ is pyridinyl or pyrimidinyl, which areunsubstituted or substituted by one or two substituents selected fromthe group consisting of cyclopropyl, ethyl and methyl which isunsubstituted or substituted by hydroxy. In still another embodiment thecomposition of the invention comprises a compound of formula I wherein Xis a single bond; Y is —CH═; R¹ is Cl or F, CH₃, CF₃, OCF₃, or phenyl,which is substituted by fluoro; R² is hydrogen, methyl, ethyl,cyclopropylmethoxy, methoxyethoxy, Cl, N(CH₃)₂, CF₃, OCH₂CF₃; and R³ ispyrimidinyl or pyridinyl which is unsubstituted or substituted by one ortwo substituents selected from the group consisting of ethyl and methylwhich is unsubstituted or substituted by hydroxy.

In one embodiment the composition of the invention comprises a compoundof formula I selected from:

8-methyl-4-(3-pyridin-3-yl-phenyl)-7-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

8-methyl-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-7-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one,

4-(3-pyridin-3-yl-phenyl)-7-(2,2,2-trifluoro-ethoxy)-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-8-methyl-7-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one,

7,8-dichloro-4-(3-pyridin-3-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

8-chloro-4-(3-pyridin-4-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

8-chloro-4-(3-pyridin-4-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

7,8-dichloro-4-(3-pyridin-4-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

8-chloro-7-methyl-4-(3-pyridin-3-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

8-chloro-4-(3-pyridin-3-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

8-chloro-4-[3-(6-methyl-pyridin-3-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

8-chloro-4-[3-(2-methyl-pyridin-3-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

8-chloro-7-methyl-4-(3-pyridin-4-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

7,8-dichloro-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

8-chloro-7-methyl-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

8-fluoro-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

8-chloro-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-7-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one,

8-chloro-4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-methyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,

7,8-dichloro-4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

7-dimethylamino-4-(3-pyridin-3-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,

7-dimethylamino-4-(3-pyridin-4-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,

4-(3-pyridin-4-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

4-(3-pyridin-3-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

4-(3-pyridin-3-yl-phenyl)-7-(2,2,2-trifluoro-ethoxy)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

7-ethoxy-4-(3-pyridin-4-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

4-(3-pyridin-4-yl-phenyl)-7-(2,2,2-trifluoro-ethoxy)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

7-methyl-4-(3-pyridin-4-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

8-methyl-4-(3-pyridin-4-yl-phenyl)-7-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

7-chloro-4-(3-pyridin-4-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

7-methyl-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one,

4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one,

7-dimethylamino-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one,

4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one,

4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydrobenzo-[b][1,4]diazepin-2-one,

7-chloro-4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one,

4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-(2,2,2-trifluoro-ethoxy)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-ethoxy-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

4-[3-(2-ethyl-pyridin-4-yl)-phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one,

4-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,

7-methyl-4-(3-pyridin-3-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

7-methoxy-4-(3-pyridin-3-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

7-ethoxy-4-(3-pyridin-3-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

7-cyclopropylmethoxy-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

7-ethyl-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-ethyl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

4-[3-(2-ethyl-6-methyl-pyridin-4-yl)-phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

4-[3-(2-hydroxymethyl-pyridin-4-yl)-phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one,

8-(2-fluoro-phenyl)-4-[3-(2-methyl-pyridin-3-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

8-(2-fluoro-phenyl)-4-(3-pyridin-4-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

8-(2-fluoro-phenyl)-4-(3-pyridin-3-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

8-(2-fluoro-phenyl)-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethoxy-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

8-chloro-7-methyl-4-(3-pyrazin-2-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

7-methyl-4-(3-pyrazin-2-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

7-(methyl-propyl-amino)-4-(3-pyrazin-2-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

8-chloro-7-methyl-4-(3-pyridazin-4-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

7-methyl-4-(3-pyridazin-4-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

8-(2-fluoro-phenyl)-4-(3-pyrimidin-5-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

4-[3-(6-methyl-pyrimidin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,

4-[2,3′]bipyridinyl-4-yl-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,and

7-methyl-4-(2′-methyl-[2,4′]bipyridinyl-4-yl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one.

In another embodiment the composition of the present invention comprisesa compound of formula I selected from

7-dimethylamino-4-(3-pyridin-3-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,

7-dimethylamino-4-(3-pyridin-4-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,

4-(3-pyridin-4-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

8-chloro-4-(3-pyridin-4-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

4-(3-pyridin-3-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

4-(3-pyridin-3-yl-phenyl)-7-(2,2,2-trifluoro-ethoxy)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

7-ethoxy-4-(3-pyridin-4-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

7-ethoxy-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

7-methyl-4-(3-pyridin-4-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

8-chloro-7-methyl-4-(3-pyridin-4-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

7-chloro-4-(3-pyridin-4-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

7,8-dichloro-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

8-(2-fluoro-phenyl)-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

8-chloro-7-methyl-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

7-methyl-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

8-methyl-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-7-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one,

8-fluoro-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

8-chloro-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-7-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one,

8-chloro-4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-methyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,

4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one,

4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-8-methyl-7-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

7-chloro-4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

7,8-dichloro-4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-(2,2,2-trifluoro-ethoxy)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-ethoxy-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

4-[3-(2-ethyl-pyridin-4-yl)-phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

4-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,

7-methyl-4-(3-pyridin-3-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

7-methoxy-4-(3-pyridin-3-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,

7-ethoxy-4-(3-pyridin-3-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethoxy-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

7-cyclopropylmethoxy-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

7-ethyl-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-ethyl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

4-[3-(2-ethyl-6-methyl-pyridin-4-yl)-phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

4-[3-(2-hydroxymethyl-pyridin-4-yl)-phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one,

4-[2,3′]bipyridinyl-4-yl-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,

7-methyl-4-(2′-methyl-[2,4′]bipyridinyl-4-yl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,and

4-[3-(6-methyl-pyrimidin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one.

In one embodiment the present invention is directed to a pharmaceuticalcomposition comprising4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one and donepezil hydrochloride.

The compounds of general formula I and their pharmaceutically acceptablesalts can be manufactured according to a process, which comprises

-   a) reacting a compound of formula II

with a compound of formula IV or IVa

wherein R is ethyl or butyl, to a compound of formula III

which subsequently undergoes deprotection of the amino group andcyclization, and, if desired,converting the compound obtained into a pharmaceutically acceptable acidaddition salt.

In more detail, according to scheme A, compounds of general formula I,in which X, Y, R¹, R² and R³ are as described above, can be preparedfrom compounds of general formula II via anacylation-deprotection-cyclization sequence:

Reacting compounds of general formula II with a dioxinone IV, in which Yand R³ are as described above, in an inert solvent such as toluene orxylene at elevated temperatures, preferably between 80° C. and 160° C.,gives rise to compounds of general formula III. Alternatively, compoundsof general formula III can also be prepared by for example reaction of acompound of general formula II with a beta-ketoester (general formulaIVa), in which Y and R³ are as described above, using the sameconditions as described for the reaction with the dioxinones.

Afterwards, cleaving the BOC (tert-butoxycarbonyl) protecting group incompounds of general formula III and concomitant cyclization of thedeprotected compound yields the desired compounds of general formula I.Any other suitable amino protecting group, such as e.g. Fmoc(9-fluorenylmethoxycarbonyl) or benzyloxycarbonyl (Z), can bealternatively used instead of the BOC group.

The deprotection-cyclization step can be carried out by treating thecompounds of general formula III with for example a Bronsted acid suchas trifluoroacetic acid (TFA) in an inert solvent such asdichloromethane (DCM). The reaction is preferably carried out attemperatures between 0° C. and 50° C. It may be advantageous to use alsoanisole or 1,3-dimethoxybenzene as a carbocation scavenger in thereaction mixture.

Compounds of general formula II, in which R¹, R² and X are as describedabove can be prepared according to scheme B, by reducing the nitro groupin compounds of general formula VIa to the amino group. The reductioncan for example be carried out using hydrogen gas in presence of asuitable catalyst like for example Raney-Nickel or Palladium on carbon.Another possible reduction method is using stannous(II)chloride(SnCl₂.2H₂O) in ethanol at temperatures between 70° C. and 80° C. (asdescribed in Tetrahedron Lett. 25:839 (1984), or alternatively in polaraprotic solvents, like DMF, DMA or NMP and the like, optionally in thepresence of bases, like for example pyridine or triethylamine and thelike, at temperatures between 0° C. and 80° C. Another suitable methodis using zinc-powder in the presence of ammonium chloride in proticsolvents like, e.g., water or ethanol at temperatures between 20° C. and80° C. The exact conditions for the respective compounds of generalformula II can be found in the experimental part.

The protection of the amino function can be applied to a number ofcommercially available starting materials or compounds synthesized byanyone skilled in the art to produce the corresponding 2-nitroanilineswith the general formula VI, in which X is a single bond and R¹ and R²are as described above.

wherein R² is Cl, F, OR″ and R′ is H in formula VIIa (general procedure,methods a, b or c below) and Ac in formula IXa (general procedure,method d below).

Reaction conditions are:

-   method a: diphosgene, EtOAc, 77° C.; then t-BuOH-   method b: Boc₂O, Cs₂CO₃, 2-butanone, 52° C.-   method c: i) Boc₂O, DMAP, THF; ii) TFA, DCM, 0° C.-   method d: i) Boc₂O, DMAP, THF; ii) NH₄OH, THF

As described in scheme C, compounds of the general formula VIa, in whichR¹ is as described above, R² is chloro, fluoro or substituted oxygen andR′ is hydrogen, can be prepared by protection of the amino group ofcompounds of the general formula VIIa, in which R¹ is as describedabove, R² is chloro, fluoro or substituted oxygen and R′ is hydrogen,with a tert-butoxycarbonyl-group (BOC). One possibility for theprotection of the amino function is for example reacting compounds ofgeneral formula VIIa with di-tert-butyl-carbonate in the presence of abase such as cesium carbonate. The reaction can be carried out in polarsolvents such as acetone or butanone and the like at temperaturesbetween 20° C. and 80° C.

Alternatively, the protection of the amino group can be achieved bypreparing the intermediate isocyanate by treatment of compounds of thegeneral formula VIIa, in which R¹ is as described above, R² is chloro,fluoro or substituted oxygen and R′ is hydrogen, with diphosgene,preferably in aprotic solvents such as EtOAc or 1,4-dioxane attemperatures from 0° C. to 100° C., and subsequent treatment of theisocyanate with tert-butanol in solvents such as dichloromethane or1,2-dichloroethane and the like at temperatures between 20° C. and 85°C. to give the desired compounds of general formula VIa.

Another suitable method to achieve this protection step is theintermediate formation of a di-BOC compound by treatment of compounds ofthe general formula VIIa, in which R¹ is as described above, R² ischloro, fluoro or substituted oxygen and R′ is hydrogen, withdi-tert-butyl-carbonate in the presence of DMAP in an aprotic solventsuch as tetrahydrofuran and the like, followed by selective removal of asingle BOC-group by treatment with a Bronsted-acid, like e.g. TFA, inaprotic solvents such as dichloro-methane, chloroform or1,2-dichloroethane at temperatures between 0° C. and 20° C. to give thedesired compounds of general formula VIa.

Yet another suitable method to produce compounds of general formula XIais the intermediate formation of a N—Ac—BOC compound by treatment ofcompounds of the general formula IXa, in which R¹ is as described above,R² is chloro or fluoro and R′ is acetyl, with di-tert-butyl-carbonate inthe presence of DMAP in an aprotic solvent such as tetrahydrofuran andthe like, followed by selective removal of a single BOC-group bytreatment with a Bronsted-base, like e.g. aqueous ammonia (NH₄OH), inaprotic solvents such as tetrahydrofuran, diethylether or 1,4-dioxaneand the like, at temperatures between 0° C. and 20° C. to give thedesired compounds of general formula VIa.

The protection of the amino function as shown in scheme C can be appliedto a number of commercially available starting materials or compoundssynthesized by standard transformations [e.g. nitration followed byselective ammonolysis of the halide in ortho-position to the newlyintroduced nitro-group as described in J. Med. Chem. 37:467 (1994); orortho-nitration of acetanilide-compounds followed by deacetylation withfor example. aqueous potassium hydroxide solution or aqueoushydrochloric acid as described in Org. Synth. 25:78 (1945) or in J. Med.Chem. 28:1387 (1985)] known to one skilled in the art to produce thecorresponding 2-nitroanilines with the general formula VIIa, in which R¹is as described above, R² is chloro br fluoro and R′ is hydrogen, or2-nitroacetanilides with the general formula IXa, in which R¹ is asdescribed above, R² is chloro or fluoro and R′ is acetyl. The exactconditions for the respective compounds used in this invention can befound in the experimental part.

According to scheme D, compounds of general formula II in which R¹ isphenyl optionally substituted as described above for compounds where Xis a single bond and R² is as described above, can be prepared bydifferent routes depending on the nature of R¹ from the iodo-compoundsof general formula V, in which R² is as described above. As shown inscheme D, the key step is a coupling reaction of Suzuki-type to producecompounds of the general formula VIb.

Compounds of general formula V, in which R² is as described above, canbe prepared by different routes depending on the individual residue R².For example, a compound of formula V wherein R² is Cl, can be preparedfrom the commercially available 5-chloro-2-nitroaniline by iodinationusing iodine monochloride in acetic acid in the presence of sodiumacetate at temperatures between 20° C. and 80° C. to give5-chloro-4-iodo-2-nitroaniline, which in turn can be protected to yielda compound of formula V wherein R² is Cl.

According to scheme E, compounds of general formula VIb, in which R¹ ispyrrol-1-yl, X is a single bond and R is chloride, can be prepared fromknown 5-chloro-2-nitro-1,4-phenylenediamine [CAS-No. 26196-45-2] byselective condensation of the 4-amino-group with a suitable substituted2,5-dimethoxy-tetrahydrofuran of the general formula VIII, as describedin J. Heterocycl. Chem. 25:1003 (1988).

The reaction is preferably carried out in acidic media, like for exampleacetic acid or propionic acid and the like, at temperatures between 40°C. to 100° C. The exact conditions for the respective compounds can befound in the experimental part.

As shown in scheme F, compounds of general formula VIc, in which R² is—NR′R″, wherein R′ and R″ are hydrogen, (C₁–C₇)-alkyl orC₃–C₇-cycloalkyl, or:form a pyrrolidin-1-yl, piperidin-1-yl, ormorpholine-4-yl, can be prepared from the intermediate compounds withthe general formula VIc (which individual synthesis can be found in theexperimental part) by a nucleophilic substitution reaction with therespective amines in the presence of a suitable base.

The reaction is preferably carried out in a polar, aprotic solvent suchas dimethyl formamide, N-methyl-pyrrolidone or dimethyl sulfoxide andthe like. The base can be selected from the sterically hindered aminessuch as triethylamine or Hünig's base, alkoxides such as sodiummethoxide and tert-butoxide, or hydrides such as sodium hydride. Thereaction can be performed at temperatures between 20° C. and 110° C.,depending on the individual compounds to be synthesized.

According to scheme G, compounds of general formula II in which R¹ is asdescribed above for compounds where X is an ethynediyl group can beprepared by different routes from the iodo-compounds V, depending on thenature of R¹ and R². As shown in scheme F, the transformation can forexample be carried out

-   a) by directly attaching the R¹-alkynediyl-substituent to a compound    of general formula V via a Sonogashira-type coupling to produce    compounds of the general formula VId followed by the reduction of    the nitro group, or-   b) by two stepwise Sonogashira-type couplings, in which first    trimethylsilyl-acetylene is coupled to a compound of general formula    V to yield, after desilylation with sodium hydroxide in methanol,    the intermediate X which then can be transformed via a second    Sonogashira-type coupling with the appropriate reactant R¹—I, R¹—Br    or R¹—OSO₂CF₃ into compounds of the general formula VId and    reduction of the nitro group leads to the desired compounds of    general formula II.

The exact conditions for the respective compounds can be found in theexperimental part.

According to Scheme H, the dioxinones and β-keto esters building blockswith the general formula IV and IVa can be prepared by methods known tosomeone skilled in the art from the corresponding carboxylic acidderivatives R³—R, i.e. free acids, methyl or ethyl esters, acidchlorides and nitrites. The exact conditions for the correspondingcompounds can be found in the experimental part.

The pharmaceutically acceptable addition salts can be manufacturedreadily according to methods known in the art and taking intoconsideration the nature of the compound to be converted into a salt.Inorganic or organic acids such as, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or citricacid, formic acid, fumaric acid, maleic acid, acetic acid, succinicacid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid andthe like are suitable for the formation of pharmaceutically acceptablesalts of basic compounds of formula I.

The present invention also provides a kit comprising:

-   a first compound being an AChE inhibitor and a pharmaceutically    acceptable carrier, vehicle or diluent in a first unit dosage form;-   a second compound being a mGluR2 antagonist; and a pharmaceutically    acceptable carrier, vehicle or diluent in a second unit dosage form;    and-   a container for containing said first and second unit dosage forms.    In another embodiment the present invention provides a kit    comprising:-   a first compound being an AChE inhibitor; and a pharmaceutically    acceptable carrier, vehicle or diluent in a first unit dosage form;-   a second compound being a dihydro-benzo[b][1,4]diazepin-2-one    derivative or a prodrug thereof; and a pharmaceutically acceptable    carrier, vehicle or diluent in a second unit dosage form; and-   a container for containing said first and second unit dosage forms.

In another embodiment the present invention provides a kit comprising:

-   a first compound being an AChE inhibitor; and a pharmaceutically    acceptable carrier, vehicle or diluent in a first unit dosage form;-   a second compound being a compound of formula I according to claim    3, a prodrug of said compound or isomer, or a pharmaceutically    acceptable salt or solvate of said compound,-   isomer or prodrug; and a pharmaceutically acceptable carrier,    vehicle or diluent in a second unit dosage form; and-   a container for containing said first and second unit dosage forms    wherein the amounts of said first and second compounds result in an    enhanced therapeutic effect, as described above.

The kit may further comprise a printed label or a set of printedinstructions directing the use of the composition to treat a cognitivedisorder.

The compositions of this invention may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. One or more activecompounds may be present in association with one or more non-toxicpharmaceutically acceptable carriers and/or diluents and/or adjuvantsand if desired other active ingredient. The compositions of theinvention may be suitable for oral use, e.g., as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsion, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredients inadmixture with non-toxic pharmaceutically acceptable excipients that aresuitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate sodium carbonatelactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example corn starch, gelatin or acacia; andlubricating agents, for example magnesium stearate, stearic acid ortalc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, e.g., sodium carboxymethylcellulose,methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents may be a naturally-occurring phosphatide, e.g., lecithin,or condensation products of an alkylene oxide with fatty acids, e.g.,polyoxythylene stearate, or condensation products of ethylene oxide withlong chain aliphatic alcohols, e.g., heptadecaethyleneoxycetanol, orcondensation products of ethylene oxide with partial esters derived fromfatty acids and a hexitol such as polyoxyphenylene sorbitol monooleate.The aqueous suspension may also contain one or more preservatives, e.g.,ethyl, or n-propyl p-hydroxybenzoate, one or more colouring agents, oneor more flavouring agents, and one or more sweetening agents, such assucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispensing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional exipients, e.g., sweetening, flavoring and coloring agents,may also be present. The compositions of the invention may also be inthe form of oil-in-water emulsions. The oily phase may be a vegetableoil, for example olive oil or arachis oil, or a mineral oil, for exampleliquid paraffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phospha-tides, for example soy bean, lecithin andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate.

The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, e.g.,glycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The composition of this invention may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug.

Such materials are cocoa butter and polyethylene glycols.

Active compounds may be administered parenterally in a sterile medium.The drug, depending on the vehicle and concentration used, can either besuspended or dissolved in the vehicle. Advantageously, adjuvants such aslocal anestetics, preservatives and buffering agents can be dissolved inthe vehicle.

The total dosage of the mGluR2 antagonist and the AChE inhibitor in thecombination is generally lower than the sum of the individual dosagesnormally administered and may, e.g. be in the range of from 0.01 to 10mg/kg/day, or in the range of from 0.01 to 5 mg/kg/day, or in the rangeof from 0.01 to 2 mg/kg/day.

EXAMPLES

The compounds of formula I and their intermediates may be preparedaccording to the following procedures:

General procedure A: Preparation of (2-nitro-phenyl)-carbamic acidtert-butyl esters from 2-nitroanilines or 2-nitroacetanilides

Method a (from 2-nitroanilines): To a solution of diphosgene (4.1 mL,34.1 mmol) in EtOAc (40 mL) at 0° C. was added a solution of the2-nitroaniline (45.5 mmol) in EtOAc (200–500 mL), and the mixture washeated to reflux for 18 h. The solvent was removed in vacuum to leave abrown solid, which was triturated with hot hexane (200 mL). The solidmaterial was filtered off and the filtrate was concentrated underreduced pressure to leave the pure 2-nitrophenylisocyanate as a yellowsolid. This material was refluxed in a mixture of excess tert-BuOH inCH₂Cl₂ for 2.5 h. Removal of the solvent left an orange solid which waspurified by silica gel column chromatography with hexane/EtOAc to givethe (2-nitro-phenyl)-carbamic acid tert-butyl ester as a yellow solid.

Method b (from 2-nitroanilines): To a mixture of the 2-nitroaniline (142mmol) and cesium carbonate (55.5 g, 170 mmol) in 2-butanone (740 mL) wasdropwise added a solution of Boc₂O (37.8 g, 173 mmol) in 2-butanone (170mL) and the resulting mixture was stirred at 50° C. to 80° C. until tlcindicated complete conversion. The solvent was removed in vacuum, theresidue was treated with a mixture of H₂O (240 mL) and MeOH (240 mL) andextracted with hexane (3×500 mL). The combined hexane layer was washedwith brine (200 mL) and all aqueous layers were reextracted with hexane(300 mL). All combined hexane layers were dried over MgSO₄, filtered andthe solvent was removed in vacuum to give an orange solid, which waspurified by silica gel column chromatography with hexane/EtOAc to givethe (2-nitro-phenyl)-carbamic acid tert-butyl ester as a yellow solid.

Method c (from 2-nitroanilines): To a solution of the 2-nitroaniline(550 mmol) and DMAP (1.22 g, 10 mmol) in THF (1000 mL) at 23° C. wasdropwise added within 70 min a solution of Boc₂O (246 g, 1128 mmol) inTHF (500 mL) and stirring was continued at 23° C. for 75 min. The entiremixture was evaporated to dryness and dried at HV to leave a dark brownsolid. This material was dissolved in DCM (1100 mL), cooled to 0° C. andTFA (84 mL, 1100 mmol) was added dropwise. The mixture was stirred at 0°C. for 2 h, poured into ice cold sat. NaHCO₃-solution, extracted withDCM, washed with brine and dried over MgSO₄. Removal of the solvent invacuum left a dark brown solid which was coated on silica gel andpurified by silica gel column chromatography with hexane/EtOAc to givethe (2-nitro-phenyl)-carbamic acid tert-butyl ester as a yellow solid.

Method d (from 2-nitroacetanilides): To a solution of the2-nitroacetanilide (100 mmol) and DMAP (122 mg, 1 mmol) in THF (100 mL)at 23° C. was dropwise added within 15 min a solution of Boc₂O (22.92 g,105 mmol) in THF (100 mL) and stirring was continued at 23° C. until tlcindicated completed conversion. The entire mixture was evaporated todryness and dried at HV to leave a yellow to dark brown solid. Thismaterial was dissolved in THF (200 mL) and 25% NH₄OH (77 mL, 500 mmol)was added dropwise. The mixture was stirred at 23° C. until tlcindicated complete conversion, poured into 1N HCl-solution, extractedwith EtOAc, washed the organic layer with sat. NaHCO₃-solution andbrine, dried over MgSO₄. Removal of the solvent in vacuum left a yellowto brown solid which was generally pure enough for furthertransformation or—if necessary—coated on silica gel and purified bysilica gel column chromatography with hexane/EtOAc to give the(2-nitro-phenyl)-carbamic acid tert-butyl ester as a yellow solid.

General procedure C: Preparation of5-N-substituted-(2-nitro-phenyl)-carbamic acid tert-butyl esters

(5-Chloro or -fluoro-2-nitro-phenyl)-carbamic acid tert-butyl ester wasstirred with the desired amine optionally with DMSO, DMF, DMA, NMP orTHF and/or DIPEA or Et₃N at temperatures from 23° C. to 130° C. untiltlc indicated complete disappearance of the chloride or fluoride. Thereaction was cooled to 23° C. poured into ice-water, the precipitate wasfiltered off, washed with water and dried in vacuum. In cases were theproduct did not precipitate, the mixture was extracted with EtOAc,washed with water and brine, dried over Na₂SO₄. Filtration and removalof the solvent in vacuum left a crude product, which was—ifnecessary—purified by silica gel column chromatography with hexane/EtOActo give the pure title compound.

General procedure F: Preparation of 2-nitro-4-pyrrol-1-yl-phenylaminesby condensation of 2-nitro-1,4-phenylenediamine with2,5-dimethoxytetrahydrofuran [cf. J. Heterocycl. Chem. 25:1003–1005(1988)]

A mixture of the 2-nitro-1,4-phenylenediamine (25 mmol) and2,5-dimethoxytetra-hydrofuran (26–32.5 mmol) in HOAc (150 mL) wasstirred at 60–120° C. until tic indicated complete conversion of thephenylenediamine. After cooling to 23° C., the mixture was poured intobrine (500 mL) and extracted with EtOAc (3×200 mL). The combined organiclayers were washed with brine (300 mL) and dried over MgSO₄. Removal ofthe solvent left a brown residue, which was purified by silica gelcolumn chromatography with cyclohexane/EtOAc to give the title compound.

General procedure J: Preparation of the (2-amino-phenyl)-carbamic acidtert-butyl esters by reduction of (2-nitro-phenyl)-carbamic acidtert-butyl esters

Method a: Catalytic hydrogenation: A mixture of the nitro compound (1.0mmol) in MeOH or EtOH and THF (1:1 ca. 20 mL) [or solely EtOAc foraromatic chlorides] and 10% Palladium on carbon (20 mg), Raney-Ni (20mg) or 5% Platinum on carbon was stirred vigorously at 23° C. underhydrogen atmosphere until tlc indicated complete conversion. Thecatalyst was filtered off, washed thoroughly with MeOH or EtOH and THF(1:1) [or EtOAc], the solvent was removed in vacuum to give the titlecompound, which was generally pure enough for further transformations,but could be crystallized from hot hexane or cyclohexane if necessary.

Method b: Reduction with SnCl₂.2H₂O: A mixture of the nitro compound(1.0 mmol) and SnCl₂.2H₂O (5.0 mmol) was either stirred in EtOH (30 mL)at 70–80° C. or alternatively in pyridine (3 mL) and DMF (12 mL) at 23°C. under Argon atmosphere until tlc indicated complete conversion [cf.Tetr. Lett. 25:839 (1984)]. The reaction mixture was brought to pH 8 byaddition of sat. NaHCO₃-solution and extracted with EtOAc (2×100 mL).The combined organic layers were washed with brine and dried overNa₂SO₄. Removal of the solvent left a yellow solid, which—ifnecessary—can be purified by silica gel column chromatography.

Method c: Reduction with Zn and NH₄Cl: To a mixture of the nitrocompound (1.0 mmol) in EtOH/THF/sat. NH₄Cl-solution (1:1:1, 30 mL) wasadded Zinc dust (3.0 mmol) and the mixture was stirred at 70° C. underArgon atmosphere until tlc indicated complete conversion. Aqueous workupas described in method b.

General Procedure K

Method a): Preparation of ethyl or tert-butyl 3-aryl-3-oxo-propionates:The ethyl or tert-butyl 3-aryl-3-oxo-propionates were prepared from thearyl acid chlorides and ethyl or tert-butyl malonate potassium salt[CAS-no. 6148-64-7 and 75486-33-8]with Et₃N and MgCl₂ in CH₃CN at 0° C.to 23° C. according to Synthesis 290 (1993). If the free aryl carboxylicacid was employed in this reaction, it was activated by treatment withethyl chloroformate and Et₃N in THF/CH₃CN at 0° C. prior to reactionwith the malonate salt.

Method b): Preparation of tert-butyl 3-aryl-3-oxo-propionates: Thetert-butyl 3-aryl-3-oxo-propionates were alternatively prepared from themethyl or ethyl aryl esters by treatment with lithium tert-butyl acetate[prepared by treatment of tert-butyl acetate with lithiumdiisopropylamide in THF at −78° C.] in the presence of lithiumtert-butoxide according to Synthesis 45 (1985). If the product containedresidual starting material after workup, thus could be removed byselective saponification with LiOH in THF/MeOH/H₂O at 23° C.

Method c): Preparation of 3-aryl-3-oxo-propionic acids: The3-aryl-3-oxo-propionic acids were prepared from the aryl acid chloridesand bis(trimethylsilyl)malonate with Et₃N and LiBr in CH₃CN at 0° C.according to Synth. Commun. 15:1039 (1985) (method c1) or with n-BuLi inether at −60° C. to 0C. according to Synthesis 787 (1979) (method c2).

Method d): Preparation of ethyl or tert-butyl 3-aryl-3-oxo-propionates:The ethyl or tert-butyl 3-aryl-3-oxo-propionates were prepared from thearyl nitriles and ethyl or tert-butyl bromoacetate [CAS-No. 105-36-2 and5292-43-3] with activated Zinc dust in THF at reflux, followed bytreatment of the obtained enamino ester with 10% HCl in THF at 23° C.according to J. Org. Chem. 48:3835 (1983).

General procedure M: Preparation of{2-[3-aryl-3-oxo-propionylamino]-phenyl}-carbamic acid tert-butyl estersby reaction of (2-amino-phenyl)-carbamic acid tert-butyl esters withethyl or tert-butyl 3-aryl-3-oxo-propionates or6-aryl-2,2-dimethyl-[1,3]dioxin-4-ones

A mixture of the (2-amino-phenyl)-carbamic acid tert-butyl ester or(1.0–1.2 mmol) and (1.0–1.5 mmol) of the ethyl or tert-butyl3-aryl-3-oxo-propionate or 6-aryl-2,2-dimethyl-[1,3]dioxin-4-one washeated in toluene or xylene (4–8 mL) to 80° C. to 150° C. until tlcindicated complete consumption of the minor component. The solution wasallowed to cool to 23° C., whereupon the product generally crystallized(in cases where crystallization failed to appear it was induced byaddition of hexane or ether, alternatively the reaction mixture wasdirectly subjected to silica gel column chromatography). The solid wasfiltered off, washed with ether or mixtures of ether/hexane and dried invacuum to give the {2-[3-aryl-3-oxo-propionylamino]-phenyl}-carbamicacid tert-butyl esters, which was used directly in the following stepor—if necessary—was purified by recrystallization or by silica gelcolumn chromatography.

General procedure N: Preparation of4-aryl-1,3-dihydro-benzo[b][1,4]diazepin-2-ones

A solution or suspension of the{2-[3-aryl-3-oxo-propionylamino]-phenyl}-carbamic acid tert-butyl ester(1.0 mmol) in CH₂Cl₂ (5 mL) [anisole or 1,3-dimethoxybenzene (5–15 mmol)can be added if necessary]was treated with TFA (0.5–5.0 mL) at 0° C. andstirring was continued at 23° C. until tlc indicated completeconsumption of the starting material.

Workup procedure a: The solvent was removed in vacuum, the residuetreated with little ether, whereupon it crystallized. The solid wasstirred with sat. NaHCO₃-solution or 1M Na₂CO₃-solution, filtered,washed with H₂O and ether or mixtures of ether/THF/MeOH and was dried togive the title compound, which if necessary can be purified bycrystallization from 1,4-dioxane or by silica gel column chromatographywith cyclohexane/EtOAc or EtOAc/EtOH.

Workup procedure b: The reaction mixture was diluted with DCM or EtOAc,washed with sat. NaHCO₃-solution or 1M Na₂CO₃-solution, brine and driedover MgSO₄ or Na₂SO₄. Removal of the solvent in vacuum left a material,which could be triturated with ether or mixtures of ether/THF/MeOH togive the title compound, or which if necessary can be purified bycrystallization from 1,4-dioxane or by silica gel column chromatographywith cyclohexane/EtOAc or EtOAc/EtOH.

In the following examples the following abbreviations were used: RT:room temperature; TFA: trifluoroacetic acid; TFAA: trifluoroaceticanhydride

Example F1 2-Nitro-4-pyrrol-1-yl-phenylamine (Compound F1)

Compound F1 was prepared from 2-nitro-1,4-phenylenediamine [CAS-No.5307-14-2) (20 g, 131 mmol) and 2,5-dimethoxytetrahydrofuran (18.3 mL,135 mmol) in HOAc (37 ml) at 95° C. for 3 h according to the generalprocedure F.

Example A1 (5-Chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acidtert-butyl ester (Compound A1)

Compound A1 was prepared via the di-Boc-compound from commerciallyavailable 5-chloro-2-nitro-4-trifluoromethyl-phenylamine [CAS-No.35375-74-7](22.61 g, 94 mmol) and Boc₂O (42.06 g, 193 mmol), followed bytreatment with 2 eq. TFA in CH₂Cl₂ according to the general procedure A(method c).

The following compounds were prepared in analogy to the method asdescribed in Example A1:

Compound name and number Starting compound(4-fluoro-2-nitro-phenyl)-carbamic acid tert-butyl4-fluoro-2-nitroaniline ester (A2)(2-nitro-4-trifluoromethyl-phenyl)-carbamic acid 4-amino-3- tert-butylester (A3) nitrobenzotrifluoride(5-chloro-4-methyl-2-nitro-phenyl)-carbamic acid 5-chloro-4-methyl-2-tert-butyl ester (A4) nitroaniline

Example A5 (5-Fluoro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acidtert-butyl ester (Compound A5)

Compound A5 was prepared via the di-Boc-compound from5-fluoro-2-nitro-4-tri-fluoromethyl-phenylamine [which was prepared fromcommercially available 4-amino-2-fluorobenzotrifluoride by acetylationwith Ac₂O in toluene at 23° C., followed by nitration with 100% nitricacid from 10–23° C. and deacetylation with 2N NaOH in THF at 50° C.](5.21 g, 23.2 mmol) and Boc₂O (10.63 g, 48.7 mmol). After treatment with2 eq. TFA in CH₂Cl₂ according to the general procedure A (method c)compound A5 was obtained.

Example A6 (4-Chloro-2-nitro-phenyl)-carbamic acid tert-butyl ester(Compound A6)

Compound A6 was prepared via the isocyanate from commercially available4-chloro-2-nitro-phenylamine [CAS-No. 89-63-4] (5.0 g, 29 mmol) withdiphosgene (1.75 mL, 14.5 mmol) in EtOAc (60 mL), followed by treatmentwith tert-BuOH (30 mL) in CH₂Cl₂ (60 mL) according to the generalprocedure A (method a).

Example A7[2-Nitro-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamicacid tert-butyl ester (Compound A7)

Compound A7 was prepared via the di-Boc-compound from2-nitro-5-(2,2,2-tri-fluoro-ethoxy)-4-trifluoromethyl-phenylamine[prepared by stirring commercially available5-chloro-2-nitro-4-trifluoromethyl-phenylamine [CAS-No. 35375-74-7],2,2,2-tri-fluoroethanol and KOH in DMSO at 23° C. for 32.5 days] andBoc₂O, followed by treatment with 2 eq. TFA in CH₂Cl₂ according to thegeneral procedure A (method c).

Example A8 (5-Methoxy-2-nitro-4-trifluoromethyl-phenyl)-carbamic acidtert-butyl ester (Compound A8)

Compound A8 was prepared via the di-Boc-compound from5-methoxy-2-nitro-4-trifluoromethyl-phenylamine [prepared by stirringcommercially available 5-chloro-2-nitro-4-trifluoromethyl-phenylamine[CAS-No. 35375-74-7], methanol and KOH in DMSO at 23° C. for 10 days](4.14 g, 17.5 mmol) and Boc₂O (8.04 g, 36.8 mmol), followed by treatmentwith 2 eq. TFA in CH₂Cl₂ according to the general procedure A (methodc).

Example A9 (5-Ethoxy-2-nitro-4-trifluoromethyl-phenyl)-carbamic acidtert-butyl ester (Compound A9)

Compound A9 was prepared via the di-Boc-compound from5-ethoxy-2-nitro-4-trifluoromethyl-phenylamine [prepared by stirringcommercially available-5-chloro-2-nitro-4-trifluoromethyl-phenylamine[CAS-No. 35375-74-7], ethanol and KOH in DMSO at 60° C. for 7 days](4.16 g, 16.6 mmol) and Boc₂O (7.62 g, 34.9 mmol), followed by treatmentwith 2 eq. TFA in CH₂Cl₂ according to the general procedure A (methodc).

Example A10 (5-Methyl-2-nitro-4-trifluoromethyl-phenyl)-carbamic acidtert-butyl ester (Compound A10)

To a suspension of (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamicacid tert-butyl ester (Compound A1) (5.00 g, 14.7 mmol),tetrakis(triphenylphosphine)palladium (1.70 g, 1.47 mmol) and potassiumcarbonate (6.09 g, 44.1 mmol) in dioxane/water (9:1; 50 ml) was added atRT trimethylboroxine (2.04 ml, 14.7 mmol). The reaction mixture wasstirred under reflux conditions for 15 h, filtered, evaporated andpurified by column chromatography on silica gel (hexane/ethyl acetate9:1) to yield compound A10.

Example A11: (4-Methyl-2-nitro-5-trifluoromethyl-phenyl)-carbamic acidtert-butyl ester (Compound A11)

N-(4-Methyl-3-trifluoromethyl-phenyl)-acetamide Acetylation ofcommercially available 4-methyl-3-trifluoromethyl-aniline (10 g, 57.1mmol) with acetic acid anhydride in toluene at RT gaveN-(4-methyl-3-trifluoro-methyl-phenyl)-acetamide [CAS 22957-86-4].

b) N-(4-Methyl-2-nitro-5-trifluoromethyl-phenyl)-acetamide Nitration ofN-(4-methyl-3-trifluoromethyl-phenyl)-acetamide (11.6 g, 53.5 mmol) inacetic acid anhydride gave a mixture ofN-(4-methyl-2-nitro-5-trifluoromethyl-phenyl)-acetamide andN-(4-methyl-2-nitro-3-trifluoromethyl-phenyl)-acetamide. Separation ofthis mixture by column chromatography on silica gel (hexane/ethylacetate 2:1) yieldedN-(4-methyl-2-nitro-5-trifluoromethyl-phenyl)-acetamide (5.2 g, 37%).

c) (4-methyl-2-nitro-5-trifluoromethyl-phenyl)-carbamic acid tert-butylester Reaction ofN-(4-methyl-2-nitro-5-trifluoromethyl-phenyl)-acetamide (5.0 g, 19.1mmol) with Boc-anhydride (4.37 g, 20.0 mmol) according to the generalprocedure A (method d) and subsequent reaction with ammonium hydroxide(25%; 5.87 ml, 38.1 mmol) gave after aqueous work up and purification bycolumn chromatography on silica gel (hexane/ethyl acetate 4:1) compoundA11.

Example A12 (4-Chloro-2-nitro-5-trifluoromethyl-phenyl)-carbamic acidtert-butyl ester (Compound A12)

Reaction of N-(4-chloro-2-nitro-5-trifluoromethyl-phenyl)-acetamide [CAS157554-77-3] (4.02 g, 14.2 mmol) with Boc-anhydride (3.26 g, 14.9 mmol)according to the general procedure A (method c) and subsequent reactionwith ammonium hydroxide (25%; 4.38 ml, 28.4 mmol) gave after aqueouswork up and purification by column chromatography on silica gel(hexane/ethyl acetate 4:1) compound A12.

Example A13 (2-Nitro-4-trifluoromethoxy-phenyl)-carbamic acid tert-butylester (Compound A13)

Reaction of commercially availableN-(2-nitro-4-trifluoromethoxy-phenyl)-acetamide CAS-No.[787-57-5] (10.0g, 37.6 mmol) with Boc-anhydride (8.68 g, 39.7 mmol) according to thegeneral procedure A (method c) and subsequent reaction-with ammoniumhydroxide (25%; 11.7 ml, 75.7 mmol). gave after aqueous work up andpurification by column chromatography on silica gel (cyclohexane/ethylacetate 4:1) compound A13.

Example A14(5-Cyclopropylmethoxy-2-nitro-4-trifluoromethyl-phenyl)-carbamic acidtert-butyl ester (Compound A14)

Compound A14 was prepared via the di-Boc-compound from5-cyclopropyl-meth-oxy-2-nitro-4-trifluoromethyl-phenylamine [preparedby stirring commercially available5-chloro-2-nitro-4-trifluoromethyl-phenylamine [CAS-No. 35375-74-7],(hydroxy-methyl)cyclopropane and KOH in DMSO at 23° C. for 4 days and at60° C. for 7 days] (4.49 g, 16.3 mmol) and Boc₂0 (7.45 g, 34.1 mmol),followed by treatment with 2 eq. TFA in CH₂Cl₂ according to the generalprocedure A (method c).

Example A15 (2-Nitro-4-trifluoromethyl-5-vinyl-phenyl)-carbamic acidtert-butyl ester (Compound A15)

A suspension of (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamicacid tert-butyl ester (Compound A1) (6.8 g, 20 mmol), vinyl boronic acid[CAS-No. 4363-34-2] {Bull. Soc. Chim. Fr. 8:2557–64 (1966)} (4.312 g, 60mmol) and K₂CO₃ (8.29 g, 60 mmol) in water (10 mL) and dioxane (50 mL)was purged by Ar-stream at 23° C. for 10 min, thentetrakis(triphenylphosphine) palladium(0) (693 mg, 0.6 mmol) was addedand the mixture was heated to 100° C. for 20 h, filtered, evaporated andpurified by column chromatography on silica gel (hexane/ethyl acetate9:1) to yield compound A15.

Example A16 (2-Nitro-4-pyrrol-1-yl-phenyl)-carbamic acid tert-butylester (Compound A16)

Compound A16 was prepared via the di-Boc-compound from2-nitro-4-pyrrol-1-yl-phenylamine (F1) (13.5 g, 66.4 mmol) and Boc₂O(30.45 g, 139 mmol), followed by treatment with 2 eq. TFA in CH₂Cl₂according to the general procedure A (method c).

Example C1 (5-Dimethylamino-2-nitro-4-trifluoromethyl-phenyl)-carbamicacid tert-butyl ester (Compound C1)

Compound C1 was prepared from(5-fluoro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butylester (A5) (1.62 g, 5.0 mmol) and dimethylamine (5.6 N in EtOH, 4.47 mL,25.0 mmol) in DMSO (10 mL) at 23° C. according to the general procedureC.

Example J1 (2-Amino-4-chloro-phenyl)-carbamic acid tert-butyl ester(Compound J1)

Compound J1was prepared from (4-chloro-2-nitro-phenyl)-carbamic acidtert-butyl ester (A6) (22.12 g, 85 mmol) by reduction with SnCl₂.2H₂Oaccording to the general procedure J (method b).

The following compounds were prepared in analogy to the method asdescribed above:

Compound name and number from(2-amino-5-chloro-4-trifluoromethyl-phenyl)-carbamic acid tert- A1 butylester (J2) (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butylA4 ester (J3) (2-amino-4-chloro-5-trifluoromethyl-phenyl)-carbamic acidtert- A12 butyl ester (J4) from: starting compound

Example J5 (2-Amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamicacid tert-butyl ester (Compound J5)

Compound J5 was prepared from(5-dimethylamino-2-nitro-4-trifluoromethyl-phenyl)-carbamic acidtert-butyl ester (C1) by hydrogenation with 10% Pd/C according to thegeneral procedure J (method a).

The following compounds were prepared in analogy to the method asdescribed above using an appropriate catalyst:

Compound name and number from (2-amino-4-fluoro-phenyl)-carbamic acidtert-butyl ester (J6) A2 (2-amino-4-trifluoromethyl-phenyl)-carbamicacid tert-butyl A3 ester (J7)[2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]- A7carbamic acid tert-butyl ester (J8)(2-amino-5-methoxy-4-trifluoromethyl-phenyl)-carbamic acid tert- A8butyl ester (J9) (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamicacid tert- A9 butyl ester (J10)(2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert- A10butyl ester (J11) (2-amino-4-methyl-5-trifluoromethyl-phenyl)-carbamicacid tert- A11 butyl ester (J12)(2-amino-4-trifluoromethoxy-phenyl)-carbamic acid tert- A13 butyl ester(J13) (2-amino-5-cyclopropylmethoxy-4-trifluoromethyl-phenyl)- A14carbamic acid tert-butyl ester (J14)(2-amino-5-ethyl-4-trifluoromethyl-phenyl)-carbamic acid tert- A15 butylester (J15) (2-amino-4-pyrrol-1-yl-phenyl)-carbamic acid tert-butylester (J16) A16 from: starting compound

Example K1 3-Oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butylester (Compound K1)

Compound K1 was prepared from 3-pyridin-3-yl-benzoic acid methyl ester[CAS-No. 79601-27-7] (1.00 g, 4.69 mmol) by treatment with lithiumtert-butyl acetate according to general procedure K (method b).

3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester(Compound K2) was prepared according to the method as described above,starting from 3-pyridin-4-yl-benzoic acid methyl ester.

Example K3 3-[3-(6-Methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acidtert-butyl ester (Compound K3)

Compound K3 was prepared from 3-(6-methyl-pyridin-3-yl)-benzoic acidmethyl ester [prepared by the following procedure: A mixture of3-carboxyphenylboronic acid (4.82 g, 29.07 mmol) and3-bromo-2-methylpyridine (5.00 g, 29.07 mmol) in acetonitrile (145 mL)and 0.4M Na₂CO₃-solution (145 mL) was degassed and Pd(Ph₃P)₄ (1.68 g, 5mol %) was added. The reaction mixture was refluxed for 16 h, evaporatedto dryness (cf. Synlett 6:829–831 (2000). The residue was suspended inMeOH (400 mL) and SOCl₂ (10.5 mL, 145 mmol) was added dropwise at 23° C.and the reaction mixture was refluxed for 4 h. Evaporated to dryness,taken up in EtOAc, washed with sat. NaHCO₃-solution and brine, driedover Na₂SO₄. Removal of the solvent in vacuum left a brown oil, whichwas purified by silica gel column chromatography withcyclohexane/EtOAc.] (3.87 g, 17.0 mmol) by treatment with lithiumtert-butyl acetate according to general procedure K (method b). Startingfrom 3-(2-methyl-pyridin-4-yl)-benzoic acid methyl ester, prepared inanalogy to the method described above,3-[3-(2-Methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butylester (Compound K4) was prepared in analogy to the above method.

Example K5 3-[3-(2,6-Dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acidtert-butyl ester (Compound K5)

Compound K5 was obtained from 3-(2,6-dimethyl-pyridin-4-yl)-benzonitrile[prepared by the following procedure: A mixture of 3-cyanophenylboronicacid [CAS-No. 150255-96-2] (4.74 g, 32.25 mmol),4-bromo-2,6-dimethylpyridine[Chem. Pharm. Bull. 38:2446 (1990) and J.Org. Chem. 27:1665 (1962)] (5.00 g, 26.87 mmol) and K₃PO₄ (8.56 g, 35.78mmol) in dioxane (126 mL) was degassed and Pd(Ph₃P)₄ (1.53 g, 1.37 mmol)was added. The reaction mixture was stirred at 90° C. for 18 h.Evaporated to dryness, taken up in EtOAc, washed with sat.NaHCO₃-solution and brine, dried over Na₂SO₄. Removal of the solvent invacuum left a brown solid, which was purified by silica gel columnchromatography with cyclohexane/EtOAc.] (2.2 g, 10.6 mmol) by treatmentwith tert-butyl bromo-acetate and activated zinc, followed by hydrolysiswith 10% HCl according to general procedure K (method d).

3-[3-(2-ethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butylester (Compound K6) was prepared in analogy to the above method startingfrom 3-cyanophenylboronic acid and 4-bromo-2-ethyl-pyridine.

Example K7 3-[3-(6-Cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionicacid tert-butyl ester (Compound K7)

Compound K7 was obtained from3-(6-cyclopropyl-pyridin-3-yl)-benzonitrile [prepared by the followingprocedure: A mixture of 3-cyanophenylboronic acid [CAS-No. 150255-96-2](8.82 g, 60 mmol), crude 5-bromo-2-cyclopropylpyridine {prepared by thefollowing procedure: A mixture of 2,5-dibromopyridine (11.85 g, 50mmol), cyclopropyl zinc chloride (0.4 M in THF, 160 mL, 64 mmol),Pd(PPh₃)₄ (578 mg, 1 mol %) in THF (55 mL) was stirred under Argonatmosphere at 70° C. for 1.5 h. Cooled to RT, poured into sat.NaHCO₃-solution, extracted with ether, washed with brine, dried overNa₂SO₄. Removal of the solvent in vacuum left a brown oil (12.36 g).}(ca. 60 mmol), Pd(PPh₃)₄ (1.733 g, 3 mol %) and K₂CO₃ (13.82 g, 100mmol) in toluene (250 mL), EtOH (22 mL) and H₂O (50 mL) was stirred at80° C. for 14 h. Cooled to RT, diluted with EtOAc, washed with sat.NaHCO₃-solution and brine, dried over Na₂SO₄. Removal of the solvent invacuum left a brown solid, which was purified by silica gel columnchromatography with cyclohexane/-EtOAc.] (9.88 g, 44.87 mmol) bytreatment with tert-butyl bromoacetate and activated zinc, followed byhydrolysis with 10% HCl according to general procedure K (method d).

Example K8 3-[3-(2-Ethyl-6-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionicacid tert-butyl ester (Compound K8)

Compound K8 was obtained from3-(2-ethyl-6-methyl-pyridin-4-yl)-benzonitrile [prepared by thefollowing procedure: A mixture of 3-cyanophenylboronic acid [CAS-No.150255-96-2] (11.31 g, 76.9 mmol), 4-bromo-2-ethyl-6-methyl-pyridine[CAS-No. 155887-27-7] (12.83 g, 64.1 mmol), Pd(PPh₃)₄ (2.22 g, 3 mol %)and K₂CO₃ (17.73 g, 128.2 mmol) in toluene (360 mL), EtOH (29 mL) andH₂O (72 mL) was stirred at 80° C. for 2 h. Cooled to RT, diluted withEtOAc, washed with sat. NaHCO₃-solution and brine, dried over Na₂SO₄.Removal of the solvent in vacuum left a brown solid, which was purifiedby silica gel column chromatography with cyclohexane/EtOAc.] (12.34 g,55.5 mmol) by treatment with tert-butyl bromoacetate and activated zinc,followed by hydrolysis with 10% HCl according to general procedure K(method d).

Example K9(RS)-3-Oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionicacid tert-butyl ester (Compound K9)

Oxidation of 3-(2-methyl-pyridin-4-yl)-benzoic acid methyl ester (26.2g, 0.11 mol; K4) with H₂O₂ (30%, 31.5 ml, 0.31 mol) in acetic acid (117ml) at 70° C. for 27 h and subsequent reaction of the N-oxide in aceticacid anhydride (22 ml) at 135° C. for 30 min yielded after aqueouswork-up 3-(2-acetoxymethyl-pyridin-4-yl)-benzoic acid methyl ester.

b) Hydrolysis of crude 3-(2-acetoxymethyl-pyridin-4-yl)-benzoic acidmethyl ester (25.3 g, 0.09 mmol) with sodium methanolate (5.4M inmethanol, 5 ml) in methanol (100 ml) at RT for 48 h led after aqueouswork-up and purification by column chromatography (ethyl acetate) to3-(2-hydroxymethyl-pyridin-4-yl)-benzoic acid methyl ester (brown oil,14.7 g, 68%), which by reaction with 3,4-dihydro-2H-pyrane (9.3 ml, 0.10mol) in dichloromethane (165 ml) at RT for 22h gave after aqueouswork-up and purification by column chromatography (ethyl acetate)un-reacted material (9.46 g) and(RS)-3-[2-(tetrahydropyran-2-yloxymethyl)-pyridin-4-yl]-benzoic acidmethyl ester.

c) Reaction of(RS)-3-[2-(tetrahydropyran-2-yloxymethyl)-pyridin-4-yl]-benzoic acidmethyl ester with tert.-butyl acetate according to general procedure K(method d; example K15) yielded compound K9.

Example K10 3-[3-(6-Methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acidtert-butyl ester (Compound K10)

Compound K10 was prepared from 3-(6-methyl-pyrimidin-4-yl)-benzoic acidmethyl ester [prepared by the following procedure: A solution of3-chlorocarbonyl-benzoic acid methyl ester (19.9 g, 0.1 mol) in Et₂O (20ml) was added at 5° C. to a solution of 3-oxo-butyric acid tert-butylester magnesium salt [prepared from 3-oxo-butyric acid tert-butyl ester(13.4 ml, 82 mmol) and freshly prepared magnesium ethoxide [from Mg(2.65 g, 109 mol) in ethanol (25 ml)/CCl4 (0.5 ml)] according to Helv.Chim. Acta 35:2280 (1952)]. The mixture was stirred at RT for 15 h andthen poured on sat. NH₄Cl-sol. The pH was set to 1.6 by the addition of25% HCl and the mixture was extracted with Et₂O. The orange oil (27 g)obtained was heated in toluene (400 ml) in the presence of p-TsOHmonohydrate (0.69 g, 3.6 mmol) to 100° C. for 4 h. After cooling, thesolvent was evaporated in vacuum and the residue was dissolved in AcOEt.The solution was washed with sat. NaHCO₃-sol. and brine, dried overNa₂SO₄ and evaporated in vacuum to give 3-(3-oxo-butyryl)-benzoic acidmethyl ester (15.6 g). A sample of this material (3.0 g, 13.6 mmol) wasstirred with 2N KOH (40 ml) at RT for 10 min. The mixture was acidifiedto pH 1 with 3N HCl and the precipitate was isolated by filtration andtriturated with AcOEt to give 3-(3-oxo-butyryl)-benzoic acid (2.3 g). Asolution of this material (2.2 g, 11.0 mmol) in formamide (5.3 ml, 132mmol) was heated to 180° C. for 1 h. The mixture was cooled andpartitioned between AcOEt and sat. NaHCO₃-sol. The aqueous phase wasacidified with 3N HCl to pH 2.6 and extracted with AcOEt and the crudeproduct obtained was esterified by heating in MeOH (12 ml)/4N HCl-Et₂O(3 ml) for 18 h at 40° C. to give the methyl ester as white crystals(0.33 g).] (0.8 g, 3.5 mmol) by treatment with lithium tert-butylacetate according to general procedure K (method b).

Example K11 3-[2,3′]Bipyridinyl-4-yl-3-oxo-propionic acid tert-butylester (Compound K11)

Compound K11 was prepared from [2,3′]bipyridinyl-4-carboxylic acidmethyl ester [prepared by the following procedure: A mixture ofpyridine-3-boronic acid (0.7 g, 5.7 mmol), 2-bromo-isonicotinic acid(1.15 g, 5.7 mmol) and K₂CO₃ (0.63 g, 4.6 mmol) in CH₃CN (120 mL)/H₂O(10 mL) was degassed and Pd(PPh₃)₄ (0.13 g, 0.11 mmol) was added. Themixture was stirred for 24 h at 80° C. in an atmosphere of nitrogen andthen concentrated in vacuum to a volume of ca. 10 ml. The pH was set to6.by addition of 3N HCl and the solution was then evaporated in vacuumto dryness. The residue was stirred in 1N HCl-MeOH (23 ml) for 65 h at50° C. The crude product was purified by chromatography (silica gel,AcOEt/cyclohexane 1:1) to give the methyl ester as light yellow oil(0.37 g).] (044 g, 2.1 mmol) by treatment with lithium tert-butylacetate according to general procedure K (method b).

Example K12 3-(2′-Methyl-[2,4′]bipyridinyl-4-yl)-3-oxo-propionic acidtert-butyl ester (Compound K12)

Compound K12 was prepared from 2′-methyl-[2,4′]bipyridinyl-4-carboxylicacid methyl ester [prepared by the following procedure: A cooledsolution of 4-bromo-2-methyl-pyridine (2.75 g) in Et₂O (26 ml) was addedat −78° C. over to a solution of 1.6 M butyl lithium/hexane (12 ml) inEt₂O (50 ml). The solution was stirred for 20 min at −78° C.Triisopropylborate (4.8 ml, 20.8 mmol) was added and the mixture wasallowed to warm up to RT over 1 hour and subsequently stirred for 18 h.H₂O (13 ml) was added and the layers were separated. The organic layerwas extracted with 0.5N NaOH (25 ml) and the combined aqueous layerswere acidified to pH 6 with 2N HCl and then extracted with AcOEt (200ml). The organic extract was dried and evaporated in vacuum and theresidue was triturated with Et₂O to give pyridine-2-methyl-4-boronicacid (0.36 g). A mixture of this material (0.36 g, 2.6 mmol),2-bromo-isonicotinic acid (0.53 g, 2.6 mmol) and K₂CO₃ (0.29 g, 2.1mmol) in CH₃CN (9 ml)/H₂O (4.5 ml) was degassed and Pd(PPh₃)₄ (0.12 g,0.1 mmol) was added. The mixture was stirred for 70 h at 80° C. in anatmosphere of nitrogen and then concentrated in vacuum to a volume ofca. 5 ml. The pH was set to 6 by addition of 3N HCl and the solution wasthen evaporated to dryness in vacuum. The residue was stirred in 1NHCl-MeOH (30 ml) for 20 h at 50° C. The crude product was purified bychromatography (silica gel, AcOEt/cyclohexane 1:1) to give the methylester as light yellow oil (0.22 g).] (0.16 g, 0.71 mmol) by treatmentwith lithium tert-butyl acetate according to general procedure K (methodb).

Example M1{5-Dimethylamino-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamicacid tert-butyl ester (Compound M1)

Compound M1 was prepared from(2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acidtert-butyl ester (J5) (262 mg, 0.75 mmol) and3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (K1)(223 mg, 0.75 mmol) according to the general procedure M.

The following compounds were prepared in analogy to Example M1:

Compound name and number from{5-dimethylamino-2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]- J5and K2 4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (M2){2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-4-trifluoromethyl-J7 and K2 phenyl}-carbamic acid tert-butyl ester (M3){4-chloro-2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-phenyl}- J1and K2 carbamic acid tert-butyl ester (M4){2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-trifluoromethyl-J7 and K1 phenyl}-carbamic acid tert-butyl ester (M5)[2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-5-(2,2,2-trifluoro-J8 and K1 ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butylester (M6){5-ethoxy-2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-4-trifluoromethyl-J10 and K2 phenyl}-carbamic acid tert-butyl ester (M7)(5-ethoxy-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-J10 and K4 4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (M8){5-methyl-2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-4-trifluoromethyl-J11 and K2 phenyl}-carbamic acid tert-butyl ester (M9){4-chloro-5-methyl-2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-J3 and K2 phenyl}-carbamic acid tert-butyl ester (M10){5-chloro-2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-4-trifluoromethyl-J2 and K2 phenyl}-carbamic acid tert-butyl ester (M11)(2′-fluoro-3-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-J17 and K4 biphenyl-4-yl)-carbamic acid tert-butyl ester (M12)(4-chloro-5-methyl-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-J3 and K4 phenyl)-carbamic acid tert-butyl ester (M13)(5-methyl-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-J11 and K4 4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester(M14)(2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-J7 and K4 phenyl)-carbamic acid tert-butyl ester (M15)(4-methyl-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-J12 and K4 5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester(M16)(4-fluoro-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-J2 and K4 phenyl)-carbamic acid tert-butyl ester (M17)(4-chloro-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-J4 and K4 5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (M18)(4-chloro-2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-5-methyl-3-oxo- J3and K5 propionylamino}-phenyl)-carbamic acid tert-butyl ester (M19)(2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-5-methyl-3-oxo-propionylamino}-J11 and K5 4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester(M20)(2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4- J7and K5 trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (M21)(2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-4-methyl-3-oxo-propionylamino}-J12 and K5 5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester(M22)(5-chloro-2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-J2 and K5 4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (M23)[2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5- J8and K5 (2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acidtert- butyl ester (M24)5-ethoxy-[2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-J10 and K5 4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester(M25)(2-{3-[3-(2-ethyl-pyridin-4-yl)-phenyl]-5-methyl-3-oxo-propionylamino}-J11 and K6 4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester(M26)(2-{3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-J7 and K7 trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (M27){5-methyl-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-trifluoromethyl-J11 and K1 phenyl}-carbamic acid tert-butyl ester (M28){5-methoxy-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4- J9 andK1 trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (M29){5-ethoxy-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-trifluoromethyl- J10 and K1 phenyl}-carbamic acid tert-butyl ester (M30)(2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethoxy-J13 and K4 phenyl)-carbamic acid tert-butyl ester (M31)(5-cyclopropylmethoxy-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo- J14and K4 propionylamino}-4-trifluoromethyl-phenyl)-carbamic acidtert-butyl ester (M32)(5-ethyl-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-J15 and K4 4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester(M33)(2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-J15 and K5 ethyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butylester (M34)(2-{3-[3-(2-ethyl-6-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-J11 and K8 5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butylester (M35)(RS)-[5-methyl-2-(3-oxo-3-{3-[2-(tetrahydropyran-2-yloxymethyl)- J11 andK9 pyridin-4-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (M36) from: starting compound *CompoundJ17: (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert-butyl ester

Example 17,8-Dichloro-4-(3-pyridin-3-yl-phenyl)-1,3-dihydro-benzo[b][1,4]di-azepin-2-one(Compound 1)

Compound 1 was prepared from 4,5-dichlorophenylenediamine (Compound J18)(172 mg, 0.97 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acidtert-butyl ester (K1) (289 mg, 0.97 mmol) by refluxing in xyleneaccording to the general procedure M. Obtained as an off-white solid(310 mg). MS (ISP) 382.2 [(M+H)⁺], 384 [(M+2+H)⁺] and 386 [(M+4+H)⁺]; mp241° C.

The following compounds were prepared in accordance with Example 1:

Compound name and number from MS (ISP)/mp7,8-dichloro-4-[3-(2-methyl-pyridin-4-yl)- J18 394.1phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one and K4 [(M − H)⁻] (2)221° C. 7,8-dichloro-4-[3-(2,6-dimethyl-pyridin-4-yl)- J18 410.3phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one and K5 [(M + H)⁺] (3)226° C. from: starting compound

Example 47-Dimethylamino-4-(3-pyridin-3-yl-phenyl)-8-trifluoromethyl-1,3-di-hydro-benzo[b][1,4]diazepin-2-one(Compound 4)

Compound 4 was prepared from{5-dimethylamino-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamicacid tert-butyl ester (M1) (306 mg, 0.56 mmol) by treatment with TFA inCH₂Cl₂ according to the general procedure N. Obtained as a yellow solid(162 mg). MS (ISP) 425.4 [(M+H)⁺]; mp 204° C.

In analogy to the above Example the following compounds were preparedstarting from the corresponding compounds:

Compound name and number from MS (ISP)/mp7-dimethylamino-4-(3-pyridin-4-yl-phenyl)-8-trifluoromethyl- M2 425.4[(M + H)⁺] 1,3-dihydro-benzo[b][1,4]diazepin-2-one (5) 202° C.4-(3-pyridin-4-yl-phenyl)-8-trifluoromethyl-1,3-dihydro- M3 382 [(M +H)⁺] benzo[b][1,4]diazepin-2-one (6)8-chloro-4-(3-pyridin-4-yl-phenyl)-1,3-dihydro-benzo- M4 348 [(M + H)⁺][b][1,4]diazepin-2-one (7) 350 [(M + 2 + H)⁺] 225–226° C.4-(3-pyridin-3-yl-phenyl)-8-trifluoromethyl-1,3-dihydro- M5 382 [(M +H)⁺] benzo[b][1,4]diazepin-2-one (8) 216° C.4-(3-pyridin-3-yl-phenyl)-7-(2,2,2-trifluoro-ethoxy)-8-trifluoromethyl-M6 480 [(M + H)⁺] 1,3-dihydro-benzo[b][1,4]diazepin-2-one (9) mp 217° C.7-ethoxy-4-(3-pyridin-4-yl-phenyl)-8-trifluoromethyl-1,3- M7 426.4 [(M +H)⁺] dihydro-benzo[b][1,4]diazepin-2-one (10) 206–207° C. (dec.)7-ethoxy-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl- M8 440[(M + H)⁺] 1,3-dihydro-benzo[b][1,4]diazepin-2-one (11) 236° C.7-methyl-4-(3-pyridin-4-yl-phenyl)-8-trifluoromethyl-1,3- M9 396.3 [(M +H)⁺] dihydro-benzo[b][1,4]diazepin-2-one (12) 229° C.8-chloro-7-methyl-4-(3-pyridin-4-yl-phenyl)-1,3-dihydro- M10 362.2 [(M +H)⁺] benzo[b][1,4]diazepin-2-one (13) 242° C.7-chloro-4-(3-pyridin-4-yl-phenyl)-8-trifluoromethyl-1,3- M11 414.1 [(M− H)⁻] dihydro-benzo[b][1,4]diazepin-2-one (14) 216° C.8-(2-fluoro-phenyl)-4-[3-(2-methyl-pyridin-4-yl)-phenyl]- M12 420.2 [(M− H)⁻] 1,3-dihydro-benzo[b][1,4]diazepin-2-one (15) 205° C.8-chloro-7-methyl-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-1,3- M13 376.4[(M + H)⁺] dihydro-benzo[b][1,4]diazepin-2-one (16) 215° C.7-methyl-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl- M14410.4 [(M + H)⁺] 1,3-dihydro benzo[b][1,4]diazepin-2-one (17) 229° C.4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3- M15 396.3[(M + H)⁺] dihydro benzo[b][1,4]diazepin-2-one (18) 208° C.8-methyl-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-7-trifluoromethyl- M16410.4 [(M + H)⁺] 1,3-dihydro benzo[b][1,4]diazepin-2-one (19) 215° C.8-fluoro-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-1,3-dihydro- M17 346.3[(M + H)⁺] benzo[b][1,4]diazepin-2-one (20) 200° C.8-chloro-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-7-trifluoromethyl- M18430.4 [(M + H)⁺] 1,3-dihydro benzo[b][1,4]diazepin-2-one (21) 201° C.8-chloro-4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-methyl- M19 390.3[(M + H)⁺] 1,3-dihydro-benzo[b][1,4]diazepin-2-one (22) 226° C.4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-methyl-8-trifluoromethyl- M20424.4 [(M + H)⁺] 1,3-dihydro benzo[b][1,4]diazepin-2-one (23) 229° C.4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl- M21 410.4[(M + H)⁺] 1,3-dihydro benzo[b][1,4]diazepin-2-one (24) 221° C.4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-8-methyl-7-trifluoromethyl- M22424.5 [(M + H)⁺] 1,3-dihydro benzo[b][1,4]diazepin-2-one (25) 223° C.7-chloro-4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl- M23444.3 [(M + H)⁺] 1,3-dihydro benzo[b][1,4]diazepin-2-one (26) 229° C.4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-(2,2,2-trifluoroethoxy)- M24508.3 [(M + H)⁺] 8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-232° C. 2-one (27)4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-ethoxy-8-trifluoromethyl- M25454.5 [(M + H)⁺] 1,3-dihydro-benzo[b][1,4]diazepin-2-one (28) 239° C.4-[3-(2-ethyl-pyridin-4-yl)-phenyl]-7-methyl-8-trifluoromethyl- M26424.4 [(M + H)⁺] 1,3-dihydro benzo[b][1,4]diazepin-2-one (29) 228° C.4-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-8-trifluoromethyl- M27 422.3[(M + H)⁺] 1,3-dihydro-benzo[b][1,4]diazepin-2-one (30) 179–181° C.7-methyl-4-(3-pyridin-3-yl-phenyl)-8-trifluoromethyl-1,3-dihydro- M28396.3 [(M + H)⁺] benzo[b][1,4]diazepin-2-one (31) 206–207° C.7-methoxy-4-(3-pyridin-3-yl-phenyl)-8-trifluoromethyl-1,3- M29 412.3[(M + H)⁺] dihydro-benzo[b][1,4]diazepin-2-one (32) 209–211° C.7-ethoxy-4-(3-pyridin-3-yl-phenyl)-8-trifluoromethyl-1,3-dihydro- M30426.4 [(M + H)⁺] benzo[b][1,4]diazepin-2-one (33) 219–224° C.4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethoxy- M31 412 [(M +H)⁺] 1,3-dihydro-benzo[b][1,4]diazepin-2-one (34) 200° C.7-cyclopropylmethoxy-4-[3-(2-methyl-pyridin-4-yl)-phenyl]- M32 466 [(M +H)⁺] 8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one 203° C.(35) 7-ethyl-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl- M33424 [(M + H)⁺] 1,3-dihydro-benzo[b][1,4]diazepin-2-one (36)4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-ethyl-8-trifluoromethyl- M34438 [(M + H)⁺] 1,3-dihydro-benzo[b][1,4]diazepin-2-one (37) 231° C.4-[3-(2-ethyl-6-methyl-pyridin-4-yl)-phenyl]-7-methyl-8-trifluoromethyl-M35 438 [(M + H)⁺] 1,3-dihydro-benzo[b][1,4]diazepin-2-one (38) 212° C.4-[3-(2-hydroxymethyl-pyridin-4-yl)-phenyl]-7-methyl-8-trifluoromethyl-M36 424.2 [(M − H)⁻] 1,3-dihydro benzo[b][1,4]diazepin-2-one (39) 215°C. from: starting compound

Example 404-[3-(6-Methyl-pyridin-3-yl)-phenyl]-8-pyrrol-1-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-one(Compound 40)

Compound 40 was prepared from (2-amino-4-pyrrol-1-yl-phenyl)-carbamicacid tert-butyl ester (J16) (273 mg, 1 mmol) and3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butylester (K3) (311 mg, 1 mmol) according to the general procedure M andsubsequent treatment of the crude product according to the generalprocedure N. Obtained as a yellow solid (195 mg). MS (ISP) 393.2[(M+H)⁺]; mp 213–214° C.

In analogy to the method described above the following compounds wereprepared:

Compound name and number from MS/mp 4-[2,3′]bipyridinyl-4-yl-7-methyl-J11 and (ISP) 397.2 8-trifluoromethyl-1,3-dihydro- K11 [(M + H)⁺]benzo[b][1,4]diazepin-2-one (41) 218–220° C.7-methyl-4-(2′-methyl-[2,4′]bipyridinyl- J11 and (ISN) 409.54-yl)-8-trifluoromethyl-1,3-dihydro- K12 [(M − H)⁻]benzo[b][1,4]diazepin-2-one (42) 238–240° C.4-[3-(6-methyl-pyrimidin-4-yl)-phenyl]- J7 and (ISP) 397.38-trifluoromethyl-1,3-dihydro- K10 [(M + H)⁺]benzo[b][1,4]diazepin-2-one (43) 219–220° C. from: starting compound

In the method of the invention the following mGluR2 antagonistcontaining tablets and capsules may be administered to a mammal in needthereof:

Example I Tablets

Tablets of the following composition are produced in a conventionalmanner:

mg/Tablet Active ingredient 100 Powdered. lactose 95 White corn starch35 Polyvinylpyrrolidone 8 Na carboxymethylstarch 10 Magnesium stearate 2Tablet weight 250

Example II Tablets

Tablets of the following composition are produced in a conventionalmanner:

mg/Tablet Active ingredient 200 Powdered lactose 100 White corn starch64 Polyvinylpyrrolidone 12 Na carboxymethylstarch 20 Magnesium stearate4 Tablet weight 400

Example III Capsules

Capsules of the following composition are produced:

mg/Capsule Active ingredient 50 Crystalline. lactose 60 Microcrystallinecellulose 34 Talc 5 Magnesium stearate 1 Capsule fill weight 150

The active ingredient having a suitable particle size, the crystallinelactose and the microcrystalline cellulose are homogeneously mixed withone another, sieved and thereafter talc and magnesium stearate areadmixed. The final mixture is filled into hard gelatine capsules ofsuitable size.

Example B1 Combination of a mGluR2 antagonist and an AChE inhibitoragainst a scopolamine-induced working memory deficit in the delayedmatch to position (DMTP) task in rats

Male Lister Hooded rats (Harlan, Netherlands), start weightapproximately 250 g, were trained to asymptotic performance in anoperant delayed match to position (DMTP) task, modified from theprocedure originally published by Dunnett, Psychopharmacology (Berl)87:357–63 (1985) (Higgins et al., Europ. J. Neuroscience 15:1827–1840(2002); Higgins et al., Europ. J. Neuroscience 15:911–922 (2002);Higgins et al., Neuropharmacology 44:324–241 (2003)]. All rats werehoused in groups of four in holding rooms at controlled temperature(20–22° C.) with a 12 h light/dark cycle (lights on at 0600 h). Accessto food was restricted so as to maintain 85–90% of free feeding bodyweight. Except for during testing, water was available ad libitum at alltimes. The rats were tested in Med Associates operant chambers, equippedwith 2 retractable levers positioned 7.5 cm either side of a centralfood tray. A single stimulus light (cue light) was positioned above eachlever. Aluminum barriers (5.5 cm chamber extension) were fitted withinthe chamber to separate each lever from the food magazine. The chamberswere controlled by Kestrel software (Conclusive Solutions, Harlow, UK)operating on an IBM compatible PC.

Rats were initially trained to lever press for a food reward (45 mgFormula ‘P’ pellet, Noyes, N.H.) on a continuous reinforcement (CRF)schedule with each lever presented singly an equal number of times(total 96 trials). On acquiring this behaviour the animals were nexttrained to make a matching response. Each trial consisted of a singlelever being inserted into the chamber and the illumination of theappropriate stimulus light (sample stage). The rat was required to pressthe sample lever, which then immediately retracted. A single nosepokeinto the central food tray resulted in the presentation of both leversand stimulus lights. Pressing the lever previously presented at thesample stage resulted in the delivery of a single food reward (choicestage). If the animal pressed the other lever, it was recorded as anincorrect response and was unrewarded. An incorrect response, or afailure to respond to the sample or choice levers during the 20 slimited hold (i.e. an omission), resulted in a time out period of 30 s.The next trial was signalled by illumination of the house light for a 5s period, after which the sample lever was extended. The number of suchtrials per session was 96.

Initially, the delay between the sample and choice stage was 1 s afterthe first magazine nose poke. Once the animals had learned the matchingrule (≧90% correct), the delay period was increased to 1, 2 and 4 s (32trials per delay), up to a final level of 1, 2, 4, 8, 16, 24s. Sixteentrials were run at each delay. Drug testing began once rats performed atasymptote at this final level, which typically is 8–10 weeks from thestart of training. The parameters measured include % correct (total no.correct/(total no. correct+incorrect)×100) both for the total sessionand for each delay interval. Percent correct responses at each delayinterval were analysed using an analysis of variance (ANOVA) withrepeated measures on Treatment and Delay. Total percent correctresponses were analysed using an ANOVA with repeated measures onTreatment. Post hoc tests were conducted by Newman-Keuls test.Statistical significance was accepted at P<0.05.

The experiment was conducted using a repeated measures design with eachanimal receiving each treatment according to a counterbalanced design.Animals were run 5 days/-week, with drug treatment on 2 test days perweek, separated by at least 2 days. Compound 23 and donepezilhydrochloride (Aricept) were prepared in 0.3% Tween 80 (v/v) in salinesolution (0.9% NaCl) and both were administered p.o. using anadministration volume of 5 ml/kg. Scopolamine hydrobromide was dissolvedin saline solution and was administered s.c. using an injection volumeof 1 ml/kg. Subjects were treated with Compound 23 (1 mg/kg per os bygavage) 180 min prior to testing, followed 145 min later by donepezilhydrochloride (1 mg/kg per os by gavage) and 5 min later by scopolamine(0.06 mg/kg). Scopolamine induced a significant delay-dependentreduction in percent correct responses, and a significant reduction intotal correct responses collapsed over the delay intervals. In the abovetest the combination of AChE inhibitor and mGluR2 antagonist produced areversal of the scopolamine deficit.

1. A method of treating acute or chronic neurological disorderscomprising administering to a mammal in need thereof a pharmaceuticalcomposition comprising a therapeutically effective amount of an AChEinhibitor selected from the group consisting of donepezil, rivastigmine,metrifonate, galantamine, physostigmine, tacrine, fordine, phenserine,citicoline and ganstigmine and an mGluR2 antagonist of formula I

wherein X is a single bond or an ethynediyl group; Y is —CH═ or ═N—; R¹is, in case X is a single bond, selected from hydrogen, cyano, halogen,(C₁–C₇)-alkyl, (C₁–C₇)-alkoxy, fluoro-(C₁–C₇)-alkyl,fluoro-(C₁–C₇)-alkoxy, pyrrol-1-yl, unsubstituted phenyl, and phenylsubstituted by one or two substituents selected from the groupconsisting of halogen, (C₁–C₇)-alkyl and fluoro-(C₁–C₇)-alkyl; or R¹ is,in case X is an ethynediyl group, selected from unsubstituted phenyl,and phenyl substituted by one or two substituents selected from thegroup consisting of halogen, (C₁–C₇)-alkyl and fluoro-(C₁–C₇)-alkyl; R²is selected from hydrogen, (C₁–C₇)-alkyl, (C₂–C₇)-alkenyl,(C₁–C₇)-alkoxy, halogen, —NR′R″, pyrrolidin-1-yl, piperidin-1-yl,morpholine-4-yl, fluoro-(C₁–C₇)-alkyl, fluoro-(C₁–C₇)-alkoxy, and(C₁–C₇)-alkoxy-(ethoxy)_(m); wherein m is 1, 2, 3 or 4; and R³ is asix-membered aromatic heterocycle ring containing 1 to 3 nitrogen atomsor a pyridine-N-oxide, which ring is unsubstituted or substituted by oneor two substituents selected from the group consisting of halogen,fluoro-(C₁–C₇)-alkyl, fluoro-(C₁–C₇)-alkoxy, cyano, amino,(C₁–C₇)-alkylamino, (C₁–C₇)-dialkylamino,(C₁–C₇)-alkoxy-(C₁–C₇)-alkylamino, (C₁–C₇)-hydroxy-(C₁–C₇)-alkylamino,—(CH₂)_(n)—C(O)—OR″, —(CH₂)_(n)—C(O)—NR′R″, —(CH₂)_(n)—SO₂—NR′R″,—(CH₂)_(n)—C(NH₂)═NR″, hydroxy, (C₁–C₇)-alkoxy, (C₁–C₇)-alkylthio,C₃–C₇-cycloalkyl, (C₁–C₇)-alkyl, and (C₁–C₇)-alkyl substituted by agroup consisting of fluoro, —NR′R″, hydroxy, (C₁–C₇)-alkoxy,pyrrolidin-1-yl, azetidin-1-yl, cyano and carbamoyloxy, wherein n is 0,1, 2, 3 or 4; and R′ and R″ are each independently selected fromhydrogen, (C₁–C₇)-alkyl and (C₃–C₇)-cycloalkyl; or a pharmaceuticallyacceptable salt thereof.
 2. The method according to claim 1 wherein theacute neurological disorder is Alzheimer's disease.
 3. The methodaccording to claim 1 wherein the chronic neurological disorder is mildcognitive impairment.
 4. The method according to claim 1 wherein theAChE inhibitor and the mGluR2 antagonist are administered separately. 5.The method according to claim 4 wherein the AChE inhibitor and themGluR2 antagonist are administered sequentially or simultaneously. 6.The method of claim 1 wherein the mGluR2 antagonist of formula I isselected from7-dimethylamino-4-(3-pyridin-3-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,7-dimethylamino-4-(3-pyridin-4-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,4-(3-pyridin-4-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,8-chloro-4-(3-pyridin-4-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one,4-(3-pyridin-3-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,4-(3-pyridin-3-yl-phenyl)-7-(2,2,2-trifluoro-ethoxy)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,7-ethoxy-4-(3-pyridin-4-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,7-ethoxy-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,7-methyl-4-(3-pyridin-4-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,and8-chloro-7-methyl-4-(3-pyridin-4-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one.7. The method of claim 1 wherein the mGluR2 antagonist of formula I isselected from7-chloro-4-(3-pyridin-4-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,7,8-dichloro-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,8-(2-fluoro-phenyl)-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,8-chloro-7-methyl-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,7-methyl-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,8-methyl-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-7-trifluoromethyl-1,3-dihydrobenzo-[b][1,4]diazepin-2-one,8-fluoro-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,8-chloro-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-7-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,and8-chloro-4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-methyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,and4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one.8. The method of claim 1 wherein the mGluR2 antagonist of formula I isselected from4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one,4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-8-methyl-7-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,7-chloro-4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,7,8-dichloro-4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-(2,2,2-trifluoro-ethoxy)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-ethoxy-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,4-[3-(2-ethyl-pyridin-4-yl)-phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,4-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,7-methyl-4-(3-pyridin-3-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,and7-methoxy-4-(3-pyridin-3-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one.9. The method of claim 1 wherein the mGluR2 antagonist of formula I isselected from7-ethoxy-4-(3-pyridin-3-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethoxy-1,3-dihydro-benzo[b][1,4]diazepin-2-one,7-cyclopropylmethoxy-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,7-ethyl-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-ethyl-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,4-[3-(2-ethyl-6-methyl-pyridin-4-yl)-phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,4-[3-(2-hydroxymethyl-pyridin-4-yl)-phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one,4-[2,3′]bipyridinyl-4-yl-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,7-methyl-4-(2′-methyl-[2,4′]bipyridinyl-4-yl)-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,and4-[3-(6-methyl-pyrimidin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one.10. A pharmaceutical composition comprising an AChE inhibitor selectedfrom the group consisting of donepezil, rivastigmine, metrifonate,galantamine, physostigmine, tacrine, fordine, phenserine, citicoline andganstigmine and a mGluR2 antagonist of formula I

wherein X is a single bond or an ethynediyl group; Y is —CH═ or ═N—; R¹is, in case X is a single bond, selected from hydrogen, cyano, halogen,(C₁–C₇)-alkyl, (C₁–C₇)-alkoxy, fluoro-(C₁–C₇)-alkyl,fluoro-(C₁–C₇)-alkoxy, pyrrol-1-yl, unsubstituted phenyl, and phenylsubstituted by one or two substituents selected from the groupconsisting of halogen, (C₁–C₇)-alkyl and fluoro-(C₁–C₇)-alkyl; or R¹ is,in case X is an ethynediyl group, selected from unsubstituted phenyl,and phenyl substituted by one or two substituents selected from thegroup consisting of alogen, (C₁–C₇)-alkyl and fluoro-(C₁–C₇)-alkyl; R²is selected from hydrogen, (C₁–C₇)-alkyl, (C₂–C₇)-alkenyl,(C₁–C₇)-alkoxy, halogen, —NR′R″, pyrrolidin-1-yl, piperidin-1-yl,morpholine-4-yl, fluoro-(C₁–C₇)-alkyl, fluoro-(C₁–C₇)-alkoxy, and(C₁–C₇)-alkoxy-(ethoxy)_(m); wherein m is 1, 2, 3 or 4; and R³ is asix-membered aromatic heterocycle ring containing 1 to 3 nitrogen atomsor a pyridine-N-oxide, which ring is unsubstituted or substituted by oneor two substituents selected from the group consisting of halogen,fluoro-(C₁–C₇)-alkyl, fluoro-(C₁–C₇)-alkoxy, cyano, amino,(C₁–C₇)-alkylamino, (C₁–C₇)-dialkylamino,(C₁–C₇)-alkoxy-(C₁–C₇)-alkylamino, (C₁–C₇)-hydroxy-(C₁–C₇)-alkylamino,—(CH₂)_(n)—C(O)—OR″, —(CH₂)_(n)—C(O)—NR′R″, —(CH₂)_(n)—SO₂—NR′R″,—(CH₂)_(n)—C(NH₂)═NR″, hydroxy, (C₁–C₇)-alkoxy, (C₁–C₇)-alkylthio,C₃–C₇-cycloalkyl, (C₁–C₇)-alkyl, and (C₁–C₇)-alkyl substituted by agroup consisting of fluoro, —NR′R″, hydroxy, (C₁–C₇)-alkoxy,pyrrolidin-1-yl, azetidin-1-yl, cyano and carbamoyloxy, wherein n is 0,1, 2, 3 or 4; and R′ and R″ are each independently selected fromhydrogen, (C₁–C₇)-alkyl and (C₃–C₇)-cycloalkyl; or a pharmaceuticallyacceptable addition salt thereof; and a pharmaceutically acceptableexcipient.
 11. The pharmaceutical composition of claim 10 wherein themGluR2 antagonist of formula I is selected from7-dimethylamino-4-(3-pyridin-3-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,7-dimethylamino-4-(3-pyridin-4-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,4-(3-pyridin-4-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,8-chloro-4-(3-pyridin-4-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one,4-(3-pyridin-3-yl-phenyl)-8-trifluoromethyl1,3-dihydro-benzo[b][1,4]diazepin-2-one,4-(3-pyridin-3-yl-phenyl)-7-(2,2,2-trifluoro-ethoxy)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,7-ethoxy-4-(3-pyridin-4-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,7-ethoxy-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,7-methyl-4-(3-pyridin-4-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,and8-chloro-7-methyl-4-(3-pyridin-4-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one.12. The pharmaceutical composition of claim 10 wherein the mGluR2antagonist of formula I is selected from7-chloro-4-(3-pyridin-4-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,7,8-dichloro-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,8-(2-fluoro-phenyl)-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,8-chloro-7-methyl-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,7-methyl-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,8-methyl-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-7-trifluoromethyl-1,3-dihydrobenzo-[b][1,4]diazepin-2-one,8-fluoro-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,8-chloro-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-7-trifluoromethyl-1,3-dihydrobenzo-[b][1,4]diazepin-2-one,8-chloro-4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-methyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,and4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one.13. The pharmaceutical composition of claim 10 wherein the mGluR2antagonist of formula I is selected from4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one,4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-8-methyl-7-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,7-chloro-4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,7,8-dichloro-4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-(2,2,2-trifluoro-ethoxy)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-ethoxy-8-trifluoromethyl-1,3-dihydro-benzo-[b]1,4]diazepin-2-one,4-[3-(2-ethyl-pyridin-4-yl)-phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,4-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,7-methyl-4-(3-pyridin-3-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,and7-methoxy-4-(3-pyridin-3-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one.14. The pharmaceutical composition of claim 10 wherein the mGluR2antagonist of formula I is selected from7-ethoxy-4-(3-pyridin-3-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethoxy-1,3-dihydro-benzo[b][1,4]diazepin-2-one,7-cyclopropylmethoxy-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,7-ethyl-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-ethyl-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,4-[3-(2-ethyl-6-methyl-pyridin-4-yl)-phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,4-[3-(2-hydroxymethyl-pyridin-4-yl)-phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one,4-[2,3′]bipyridinyl-4-yl-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,7-methyl-4-(2′-methyl-[2,4′]bipyridinyl-4-yl)-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,and4-[3-(6-methyl-pyrimidin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4diazepin-2-one.15. A kit comprising: a first unit dosage form comprising an AChEinhibitor selected from the group consisting of donepezil, rivastigmine,metrifonate, galantamine, physostigmine, tacrine, fordine, phenserine,citicoline and ganstigmine and a pharmaceutically acceptable excipient;a second unit dosage form comprising a mGluR2 antagonist of formula I

wherein X is a single bond or an ethynediyl group; Y is —CH═ or ═N—; R¹is, in case X is a single bond, selected from hydrogen, cyano, halogen,(C₁–C₇)-alkyl, (C₁–C₇)-alkoxy, fluoro-(C₁–C₇)-alkyl,fluoro-(C₁–C₇)-alkoxy, pyrrol-1-yl, unsubstituted phenyl, and phenylsubstituted by one or two substituents selected from the groupconsisting of halogen, (C₁–C₇)-alkyl and fluoro-(C₁–C₇)-alkyl; or R¹ is,in case X is an ethynediyl group, selected from unsubstituted phenyl,and phenyl substituted by one or two substituents selected from thegroup consisting of halogen, (C₁–C₇)-alkyl and fluoro-(C₁–C₇)-alkyl; R²is selected from hydrogen, (C₁–C₇)-alkyl, (C₂–C₇)-alkenyl,(C₁–C₇)-alkoxy, halogen, —NR′R″, pyrrolidin-1-yl, piperidin-1-yl,morpholine-4-yl, fluoro-(C₁–C₇)-alkyl, fluoro-(C₁–C₇)-alkoxy, and(C₁–C₇)-alkoxy-(ethoxy)_(m); wherein m is 1, 2, 3 or 4; and R³ is asix-membered aromatic heterocycle ring containing 1 to 3 nitrogen atomsor a pyridine-N-oxide, which ring is unsubstituted or substituted by oneor two substituents selected from the group consisting of halogen,fluoro-(C₁–C₇)-alkyl, fluoro-(C₁–C₇)-alkoxy, cyano, amino,(C₁–C₇)-alkylamino, (C₁–C₇)-dialkylamino,(C₁–C₇)-alkoxy-(C₁–C₇)-alkylamino, (C₁–C₇)-hydroxy-(C₁–C₇)-alkylamino,—(CH₂)_(n)—C(O)—OR″, —(CH₂)_(n)—C(O)—NR′R″, —(CH₂)_(n)—SO₂—NR′R″,—(CH₂)_(n)—C(NH₂)═NR″, hydroxy, (C₁–C₇)-alkoxy, (C₁–C₇)-alkylthio,C₃–C₇-cycloalkyl, (C₁–C₇)-alkyl, and (C₁–C₇)-alkyl substituted by agroup consisting of fluoro, —NR′R″, hydroxy, (C₁–C₇)-alkoxy,pyrrolidin-1-yl, azetidin-1-yl, cyano and carbamoyloxy, wherein n is 0,1, 2, 3 or 4; and R′ and R″ are each independently selected fromhydrogen, (C₁–C₇)-alkyl and (C₃–C₇)-cycloalkyl; or an isomer, or apharmaceutically acceptable salt thereof; and a pharmaceuticallyacceptable excipient; and a container for containing said first andsecond unit dosage forms.
 16. The kit of claim 15 wherein the mGluR2antagonist of formula I is selected from7-dimethylamino-4-(3-pyridin-3-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,7-dimethylamino-4-(3-pyridin-4-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,4-(3-pyridin-4-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,8-chloro-4-(3-pyridin-4-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one,4-(3-pyridin-3-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,4-(3-pyridin-3-yl-phenyl)-7-(2,2,2-trifluoro-ethoxy)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,7-ethoxy-4-(3-pyridin-4-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,7-ethoxy-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,7-methyl-4-(3-pyridin-4-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,and8-chloro-7-methyl-4-(3-pyridin-4-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one.17. The kit of claim 15 wherein the mGluR2 andtagonist of formula I isselected from7-chloro-4-(3-pyridin-4-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,7,8-dichloro-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,8-(2-fluoro-phenyl)-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,8-chloro-7-methyl-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,7-methyl-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,8-methyl-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-7-trifluoromethyl-1,3-dihydrobenzo-[b][1,4]diazepin-2-one,8-fluoro-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,8-chloro-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-7-trifluoromethyl-1,3-dihydrobenzo-[b][1,4]diazepin-2-one,8-chloro-4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-methyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,and4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one.18. The kit of claim 15 wherein the mGluR2 antagonist of formula I isselected from4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one,4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-8-methyl-7-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,7-chloro-4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,7,8-dichloro-4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one,4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-(2,2,2-trifluoro-ethoxy)-8-trifluoromethyl-1,3]-dihydro-benzo[b][1,4]diazepin-2-one,4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-ethoxy-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,4-[3-(2-ethyl-pyridin-4-yl)-phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,4-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,7-methyl-4-(3-pyridin-3-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,and7-methoxy-4-(3-pyridin-3-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one.19. The kit of claim 15 wherein the mGluR2 antagonist of formula I isselected from7-ethoxy-4-(3-pyridin-3-yl-phenyl)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethoxy-1,3-dihydro-benzo[b][1,4]diazepin-2-one,7-cyclopropylmethoxy-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,7-ethyl-4-[3-(2-methyl-pyridin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,4-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-7-ethyl-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,4-[3-(2-ethyl-6-methyl-pyridin-4-yl)-phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,4-[3-(2-hydroxymethyl-pyridin-4-yl)-phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one,4-[2,3′]bipyridinyl-4-yl-7-methyl-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one,7-methyl-4-(2′-methyl-[2,4′]bipyridinyl-4-yl)-8-trifluoromethyl-1,3-dihydro-benzo-[b][1,4]diazepin-2-one,and4-[3-(6-methyl-pyrimidin-4-yl)-phenyl]-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one.